Editor

Rongqiao He

Formaldehyde and Cognition

Second Edition 2025

Editor

Rongqiao He

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

ISBN 978-981-96-7280-6e-ISBN 978-981-96-7281-3

https://doi.org/10.1007/978-981-96-7281-3

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2017, 2025

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Preface

Formaldehyde is ubiquitous in humans and the environment and is involved in numerous biological pathways. In recent years, the roles of formaldehyde in humans have garnered increasing attention and research. Much work is being done on both exogenous and endogenous formaldehyde’s effects on human health. Our work primarily focuses on the relationship between endogenous formaldehyde and cognitive ability. In 2017, my colleagues and I authored a book titled Formaldehyde and Cognition, which served as the first edition and contained 14 chapters (He, 2017). As research on formaldehyde has deepened, scientists and medical professionals have gained a more profound understanding of formaldehyde’s functions, metabolism, related diseases, and underlying mechanisms. Here, we aim to update the book to reflect the latest advancements in the research field. The second edition has been expanded and updated in terms of its topics, with four new chapters added. We introduce new topics on endogenous formaldehyde, such as formaldehyde and catecholamine neurotransmitters (Chap. 3), formaldehyde and neuroinflammation (Chap. 12), formaldehyde in stroke and vascular dementia (Chap. 13), and formaldehyde in diabetes and cognitive impairment (Chap. 14). In addition to these four chapters, we have also updated and discussed the roles of formaldehyde in anxiety and depression. We have reviewed the effects of formaldehyde in epigenetics and discussed circadian rhythm (Chap. 4), as well as sleep patterns under different conditions, even in simulated-space hypomagnetic fields (Chap. 11). Furthermore, the other chapters have been updated as well.

Formaldehyde is closely linked to our health and daily lives, encompassing both benefits and hazards to human beings. International and domestic researchers have made significant contributions to various aspects of formaldehyde research, particularly in clinical investigations (Chap. 9). Formaldehyde and its metabolic product, formic acid, can be used to predict and prevent the progression of cognitive impairment clinically. The correlation between formaldehyde and ApoE4 has also been discussed. Currently, it is crucial to target endogenous formaldehyde to prevent cognitive impairment and manage the progression of neurodegenerative diseases. Meanwhile, the impact of exogenous formaldehyde exposure on human health and diseases resulting from environmental pollution continues to garner attention in various countries.

Interestingly, we would like to present a case involving a patient with age-related dementia over 800 years ago. A Chinese scholar named Mai Hong (1123–1202) described a patient with age-related memory disorders in YiJian Annals, Part 2, Vol.15 in Dream of Chinese Studies (http://​www.​guoxuemeng.​com/​guoxue/​554799.​html).

Cai Xu (commonly known as Yansi), who lived in Yongkang of Wuzhou, was renowned for his exceptional language skills. Whenever villagers needed to write and carve inscriptions for their parents and grandparents, they would invariably seek Xu Cai’s assistance. He never ceased reading and studying throughout his life. After retiring from his official duties, he was permitted to return to his hometown of Jian Zhou. However, in his later years, he began experiencing memory disorders without any apparent cause. His surroundings became indistinguishable to him, and he was unable to recognize his close friends, even mistaking passersby for his wife and children. Regarding his diet, he could not distinguish meat or wine. He was unable to perceive the change between day and night, including hunger and thirst. He lost the ability to write and eventually passed away three years after his illness was diagnosed.

Firstly, as described above, Xu was a capable intellectual who continued studying until the onset of his memory disorders. Secondly, his illness was characterized by unexplained memory loss without a clear pathogen but was associated with aging. There was no mention of stroke or other diseases prior to the onset of his memory loss. Thirdly, he suffered from cognitive impairment, unable to recognize old friends and family members. Fourthly, he experienced a circadian disorder, unable to distinguish between day and night. Fifthly, he lost executive function during the course of his illness. Lastly, the duration from the definitive diagnosis to his death (three years) is comparable to that of Alzheimer’s disease.

For a normal person, formaldehyde, formic acid, and other metabolites are continuously produced and removed in homeostasis. As the brain ages or in pathological situations, these molecules may accumulate chronically, leading to acidification of brain tissues as one of the secondary damage to the brain. The brain’s internal environment becomes increasingly hostile to the survival of nerve cells. This may explain why transplanted neural stem cells are ineffective in treating Alzheimer’s disease. Furthermore, the survival of neural stem cells requires various essential inducers and cofactors. The deteriorating internal environment also impairs the functions of these factors. Therefore, removing formic acid, formaldehyde, and other metabolites should improve the internal environment for nerve cells. This requires improving the function of blood microcirculation in the brain through medications, for instance, lumbrokinase (lumbropeptides) to circulation, and head massage to facilitate the drainage between lymphatic system and blood circulation probably (Chap. 18). At the same time, maintaining a healthy lifestyle, such as regularly consuming tea or water, which aids in the excretion of formaldehyde, formic acid, and other metabolites, can enhance the enjoyment of life.

I must acknowledge that there may be some shortcomings and even errors in this book, as formaldehyde is involved in a wide range of aspects, from genes to molecules, cells, organs, humans, diseases, and the human environment. Due to our limited knowledge and abilities, my coauthors and I may have inadvertently overlooked some important information and contributions of international and domestic colleagues in related chapters. For this, I sincerely apologize for any shortcomings in this book. Ultimately, we hope this book will appeal to a wide audience.

Acknowledgements

I deeply acknowledge all the authors who participated in writing this book: Ying Liu, Yan Wei, Yalan Di, Xiaping He, Qian Hua, Shirui Huo, JuanJuan Ji, Nianxin Kang, Ting Li, Yining Li, Kaili Liu, Jing Lu, Yang Lu, Qiang Min, Weichuan Mo, Lixian Mou, Min Qiang, Meihua Qu, Tao Su, Zhiqian Tong, Xiumei Wang, Beibei Wu, Mengqi Xi, Rong Xiao, Xuechao Fei, and Zijian Zhang. I am also grateful to my collaborators who have studied aldehydes in this laboratory and those mentioned in the first edition of the book.

This project was supported by grants from the National Key R&D Program of China (No.2022YFA1604504), the Key Research Program of Chinese Academy of Sciences (No. ZDBS-ZRKJZ-TLC007), the Beijing Municipal Science and Technology Project (Z161100000217141; Z161100000216137), the National Key Research and Development Program of China (2016YFC1306300), the National Basic Research Program of China (973 Program) (2012CB911004), the Natural Scientific Foundation of China (NSFC 31301880, NSFC 31270868), the Foundation of Chinese Academy of Sciences (CAS-20140909), and the Queensland-Chinese Academy of Sciences Biotechnology Fund (GJHZ201302). Note that I show my deep gratitude to all those grants mentioned above. In order to save the printing space, I would not show them in each chapter again unless otherwise specified.

Competing Financial Interests

The authors declare no competing financial interests.

Rongqiao He

Beijing, China

23 March 2025

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_1

1. Formaldehyde from Environment

Meihua Qu1, 2, Jing Lu³ and Rongqiao He4  

(1)

Translational Medical Center, Weifang Second People’s Hospital, Weifang, China

(2)

School of Life Science and Technology, Shandong Second Medical University, Weifang, China

(3)

Tianjin Institute of Infectious Diseases, The Second Hospital of Tianjin Medical University, Tianjin, China

(4)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Formaldehyde is widely present, from the universe to a single cell. It comes from our daily life, including air, food, water, clothing, and building materials. As the main material or a byproduct of industrial and commercial production, formaldehyde is the most common aldehyde in our environment. Contaminated air is a usual source of formaldehyde exposure. In general, humans spend approximately 90% of their time indoors, where there are complex mixtures of pollutants, including formaldehyde. Indoor formaldehyde exposure can be extremely dangerous, such as residential exposure to renovated homes, offices, and public places such as shopping centers and barbershops. It is worth mentioning occupational formaldehyde exposure in some factories, hospitals, and laboratories, where formaldehyde concentrations are higher and the people working are vulnerable. At the same time, outdoor formaldehyde sources should not be neglected for air exchange and transfer to indoor formaldehyde sources. Although the toxicity of formaldehyde has been extensively studied and its detection methods have been well developed, exposure to formaldehyde is still serious all over the world, especially the countries that are producing and using huge amounts of construction materials that contain and emit aldehydes. People are exposed to formaldehyde through breathing, gastric intestinal digestion, or skin contact. Exposure to formaldehyde can cause respiratory irritation, asthma, tumors, and multiple neuropsychological abnormalities or even cause death. Therefore, it is important to control any possible sources of formaldehyde and set up international standards to avoid formaldehyde insult.

Keywords

FormaldehydeToxicOccurrenceChemical characteristicsIndoor ExposureOutdoor exposureOccupational exposureDaily life exposure

Abbreviations

A

AER

Air Exchange Rate

C

CNS

Central Nervous System

CMCs

Chinese Medicine Clinics

E

ECE

Early childhood education

EFSA

European Food Safety Authority

EPA

The Environmental Protection Agency

F

FDH

Formaldehyde dehydrogenase

H

HCHO

Formaldehyde

HHS

U.S. Department of Health and Human Services

HPLC

High-performance liquid chromatography

I

IHCP

Institute for Health and Consumer Protection

I/O

Indoor/outdoor

N

NIOSH

National Institute for Occupational Safety and Health

O

OEHHA

Office of Environmental Health Hazard Assessment

OHS

Occupational health and safety

R

REL

Reference exposure level

U

UFFI

Urea-formaldehyde foam insulation

V

VOC

Volatile organic compound

1 Introduction

Formaldehyde is the smallest aldehyde with two hydrogen atoms and one oxygen atom bonded to a carbon atom in the center (CH₂O), which is a colorless, flammable gas at room temperature and has a strong odor. Exposure to formaldehyde may cause adverse health issues, as officially announced by the Environmental Protection Agency (EPA) (Environmental Protection Agency 2022). As described by the U.S. Department of Health and Human Services (HHS), formaldehyde (CAS#50-00-0) is one of the intermediate products in the oxidative reaction from methanol to carbon dioxide and water (Agency for Toxic Substances and Disease Registry, 1999, 2010; Base et al. 1999). Formaldehyde was first described in 1855 by Alexander Michailowitsch Butlerow (Brooks 2010). German chemist August Wilhelm von Hofmann technically synthesized formaldehyde in 1867 (Loeb 1892). The properties of formaldehyde were extensively investigated in the following decades (Tulpule et al. 2013).

Formaldehyde ubiquitously exists in the environment because it is primarily formed by abundant natural sources and anthropogenic activities (World Health Organization 2010). Natural formaldehyde is usually synthesized by photochemical reactions in the Earth’s primitive atmosphere or forest and bush fires that produce biomass combustion or emissions of volcanoes and molecular processes as biological decomposition (National Research Council (US) Committee to Review EPA’s Draft IRIS Assessment of Formaldehyde, 2011). Anthropogenic sources of formaldehyde include direct emissions by fuel combustion of all kinds of vehicles, plants, and combustion processes (such as power plants, incineration). In vegetable greenhouses in agriculture, the usage of nitrogen fertilizers, such as urea-aldehyde, leads to a marked increase in concentrations of formaldehyde in the breathing air of the greenhouse (Salthammer and Gunschera 2021). Moreover, formaldehyde is produced worldwide as a fixative and disinfectant as well as a preservative in consumable products (Tang et al. 2009). Thirty-seven percent formaldehyde solution is widely used as a preservative to maintain biological samples due to its ability to cross-link proteins (Fox et al. 1985; Hoffman et al. 2015; Leon and Pletcher 1995; Sekine et al. 2016; Toth and Biggin 2000).

Formaldehyde, with a characteristic pungent, irritating odor, is highly toxic to all animals, regardless of the route of exposure. Most formaldehyde exposures occur by inhalational, oral, and dermic routes. We live in an environment with formaldehyde present both indoors and outdoors; therefore, we are exposed to formaldehyde more or less when breathing. We are also exposed to formaldehyde more or less when we eat and drink. For instance, beer may contain formaldehyde at levels low enough not to impose a potential health risk (Hernandes et al. 2019). In some specific conditions, formaldehyde can enter the human body by direct skin contact. Studies have shown that formaldehyde exposure can cause multiple problems in the nervous, immune, and reproductive systems, with the consequence of systemic, developmental, genotoxic, and carcinogenic effects and even death (Acheson et al. 1984; Johannsen et al. 1986; Kerns et al. 1983; Til et al. 1989; Duong et al. 2011). Furthermore, the toxicity of formaldehyde was also extensively investigated and evaluated by researchers and government agencies (Agency for Toxic Substances and Disease Registry 1999; Binazzi et al. 2015; Bosetti et al. 2008; Madureira et al. 2016; McLaughlin 1994; Nielsen et al. 2017). In this chapter, we discuss the formaldehyde sources and exposures in the environment.

2 Formaldehyde Sources

2.1 Natural Sources of Formaldehyde

Formaldehyde can be produced naturally. Up to 90% of naturally produced formaldehyde is synthesized in the Earth’s primitive atmosphere by photochemical reactions (Pinto et al. 1980). Pinto et al. presumed that the precipitation of formaldehyde from the atmosphere provides 10¹¹ moles of organic carbon per year to the oceans (Fig. 1.1). Formaldehyde is also a component of smog produced by the reaction of oxygen and atmospheric methane and other hydrocarbons in the air under sunlight (Salthammer 2015). Snyder et al. first discovered formaldehyde as the polyatomic organic molecule in the universe (interstellar space) using the National Radio Astronomy Observatory (Snyder 1986; Weaver 1970; Zuckerman et al. 1970). Since then, formaldehyde has been detected in outer space and in many areas of the galaxy (Blair et al. 2008). Su et al. first observed air formaldehyde from the Chinese GaoFen-5 satellite and located sources of volatile organic compounds (VOCs) in the troposphere of the earth (Su et al. 2022). It is important to understand where and how this formaldehyde comes from. As a consequence of extensive interest in interstellar formaldehyde, studies dealing with extragalactic sources of formaldehyde have been conducted (Mangum et al. 2008). One of the proposed mechanisms for the formation of formaldehyde in interstellar space is the hydrogenation of iced CO (Pinto et al. 1980), shown as:

H+CO→HCO+H→H2COrate constant=9.2∗10−3s−1

Fig. 1.1

Formaldehyde precipitated from the primitive atmosphere of the earth. It was presumed that the precipitation of formaldehyde from the Earth’s primitive atmosphere by photochemical reactions provides 10¹¹ moles of organic carbon per year to the oceans

Apart from being an abiogenic compound, formaldehyde is also part of plant/atmosphere exchanges and plant physiological processes (Seco and Filella 2008). Formaldehyde is prone to breakdown in sunlight or in soil and water where bacteria are present (Zuckerman et al. 1970). Formaldehyde can be metabolized to formate by Formaldehyde dehydrogenase (FDH)/class III alcohol dehydrogenase and degraded quickly in vivo (Casanova-Schmitz et al. 1984a, b; Heck et al. 1982; Lu et al. 2020). A normal person metabolizes formaldehyde fast and does not accumulate in the body unless there is dysmetabolism of formaldehyde.

The route of formaldehyde exposure in humans mainly includes inhalation exposure (air) and dietary exposure (food and drinking) indoors and outdoors. The main source of formaldehyde exposure is indoor air, such as residential, office, occupational places, and public air, including cars and buses (Xu et al. 2017; Wallenius et al. 2022). However, a decrease in the level of outdoor formaldehyde is still required to achieve a good quality of indoor air. A balance between the Air Exchange Rate (AER) and the air humidity level is the key to ensuring low formaldehyde exposure to inhabitants (Niculita-Hirzel 2022). Outdoor formaldehyde and its impact on indoor levels have long been neglected, although indoor sources have been intensively studied. According to Liu et al., outdoor formaldehyde contributes to indoor concentrations by approximately one-quarter (Liu et al. 2019). They emphasized the major contribution of indoor sources using the indoor/outdoor (I/O) formaldehyde concentration ratio. Changes in I/O ratios showed a similar seasonal and diurnal trend, as outdoor concentrations are highest at noon on a day in the summer in a year. Recent work also showed seasonal and diurnal patterns of outdoor formaldehyde affecting indoor formaldehyde exposure and inhabitants’ health (Zhang et al. 2022a, b).

2.2 Anthropogenic Sources of Formaldehyde

Fuel combustion is a major source of formaldehyde from vehicle exhaust (Hoekman 1992), refineries, and factories of stone, clay, and glass production (ARB 1997). Road transport is responsible for over 70% of transport greenhouse gas emissions and much of the air pollution in the European Union (Suarez-Bertoa et al. 2017). As a feedstock for numerous industrial products, formaldehyde is produced in over five million tons each year (Viegas et al. 2013). Formaldehyde is widely used to synthesize formaldehyde-based resins, including urea-formaldehyde resin, phenol-formaldehyde resin, melamine resin, and other complex compounds. Formaldehyde-based resins are utilized in decorative materials, household products, textiles, and building materials (Adhikari et al. 2016; Kim et al. 2007). Urea-formaldehyde adhesives are the most widely used products to produce wood-based furniture and other materials due to their rapid curing, compatibility with additives, and low cost (Pizzi 2003). Using a satellite-based method coupled with local emission factors to estimate the hourly primary emissions of formaldehyde, Zhang et al. found that the formaldehyde formation potential of cropland fires was 26% higher than that of forest fires. That is, open biomass burning results in a significant elevation in ambient formaldehyde levels (Zhang et al. 2022a, b). Furniture with artificial boards, carpets, clothing, and even walls with paintings continually releases formaldehyde, making formaldehyde one of the major indoor pollutants (Salthammer et al. 2010). Formaldehyde is also an ingredient of numerous consumable household products, including daily use of cosmetics, dishwashing liquids, carpet cleaners, shoe-care agents, fabric softeners, glues and adhesives, lacquers, antiseptics, and even medicines. It would be necessary for consumers to know the content of formaldehyde in the materials used daily to avoid overexposure to formaldehyde. Furthermore, the application of formaldehyde is extended to food preservative processing, and it can be detected in Italian cheeses, dried foods, fish, and so on (Restani and Galli 1991).

3 Formaldehyde Inhalation Exposure

The route of formaldehyde exposure in humans mainly includes inhalation exposure and dietary exposure. Inhalation exposure to formaldehyde results from regulated and nonregulated sources as shown in Fig. 1.2 (Stranger et al. 2007). Sarigiannis et al. emphasized the regulation of the occurrence of major organic compounds classified by the European Commission’s INDEX (the project primarily focused on: INdoor air quality, Detection & EXposure assessment) strategy. Formaldehyde is regarded as the prior pollutant to be regulated due to its cancer risks when exposed in the home or indoor public buildings in European Union countries (Sarigiannis et al. 2011). Formaldehyde exposure indoors may also act as a risk factor for cognitive impairment, as reported recently (Liu et al. 2018). Some sources of formaldehyde emissions in indoor air have not yet been regulated within the European Union (Lai et al. 2006). As described by Kotzias et al., the development of a strategy leading to the identification of prior compounds, including formaldehyde, has been highlighted in their further regulation by the European Commission (Kotzias et al. 2005). Meanwhile, the exchange of sources outdoors and indoors should be considered in the regulation of formaldehyde exposure.

Fig. 1.2

Formaldehyde sources for indoor exposure. Indoor formaldehyde comes from different sources, such as outdoor air exchange, food, drink, and indoor contents. Indoor air is the most common source of formaldehyde exposure. Indoor formaldehyde exposure results from regulated and nonregulated sources in human daily life (Salthammer 2015). Effective ventilation is necessary for special working places, for instance, anatomy laboratories. The Environmental Protection Agency of the United States indicates 0.2 mg/kg body weight as the acceptable daily intake (ADI) of formaldehyde, and formaldehyde exposure over the ADI is potentially harmful to health

3.1 Indoor Formaldehyde Inhalation Exposure

Since 90% of the time is spent indoors, the concentration of formaldehyde indoors must be given considerable attention, and is crucial to adopt effective strategies to reduce it (Khoshakhlagh et al. 2024). Indoor formaldehyde inhalation exposure includes residential, office, public, and occupational exposure.

3.1.1 Indoor Residential Formaldehyde Exposure

The highest levels of airborne formaldehyde are detected in indoor air. As an important chemical widely used, formaldehyde is a very general indoor pollutant (Sekine et al. 2005; World Health Organization 2014). The major emission sources of formaldehyde indoors are interior building materials, including adhesives for walls, furniture, and textiles finished with crease-resistant fabrics (Tohmura 2001). Electric appliances such as photocopiers and laser printers are also reported to release a considerable amount of formaldehyde (Matsuo et al. 2008). The concentration of indoor formaldehyde is correlated with ventilation and the emission from interior materials. Therefore, the amount of formaldehyde emissions has become essential for indoor air pollution control (Dunky 2004).

The concentration of indoor formaldehyde is correlated with ventilation and the emission rate of formaldehyde from construction materials (Fig. 1.3). Bruinen showed that building age and urea-formaldehyde foam insulation (UFFI) usage were important factors regarding sources of formaldehyde (Institute for Health and Consumer Protection, 2005). The average concentration of formaldehyde inside the building without any specification was 79.3 μg/m³ and as high as 94 μg/m³ with UFFI compared to 32 μg/m³ without UFFI. The average concentration of formaldehyde in buildings for less than 5 years was as high as 196 μg/m³ compared to 46.8 μg/m³ for more than 5 years (Institute for Health and Consumer Protection, USA, 2005). It is recommended in Sweden that the median concentration of formaldehyde for personal exposure in the general population is 23 μg/m³ in the value range of 12–60 μg/m³ (Gustafson et al. 2005; Victorin 1998). A study carried out in Germany from 2001 to 2004 showed that the median indoor formaldehyde concentration was 28 μg/m³. Kirchner et al. monitored 567 randomly selected dwellings from 2003 to 2005 and showed that the median concentration of formaldehyde in bedrooms was 19.6 μg/m³ (Kirchner et al. 2008). The statistical concentration of formaldehyde (mean ± standard deviation [SD]) and the daily exposure rate were obtained from the Institute for Health and Consumer Protection (IHCP) (2005).

Fig. 1.3

China is going on with its constructions at a large scale and rapid speed. (Photographed by author, Beijing, China)

China is a developing country with rapid economic growth. Construction booms with a huge consumption of construction materials, including decoration materials containing formaldehyde (Salthammer et al. 2010). Furthermore, residential renovation is frequent and common in both urban and rural regions. In renovated buildings, indoor formaldehyde exposure is more serious than in older buildings because of higher emission rates from recently manufactured materials. Certain furniture, decorations, and building materials are sources of indoor formaldehyde (Du et al. 2013, 2014). Engineered wood products using urea-formaldehyde resin adhesives, such as particle board and chipboard, are important formaldehyde sources (He et al. 2012; Xing et al. 2005). Indoor pollution with formaldehyde has become serious in China (Ye et al. 2017).

Meng et al. measured 6000 recently refurbished dwellings selected from 1999 to 2006 in urban areas in China, and the results showed that the average concentration of indoor formaldehyde was 238 μg/m³, while the average outdoor formaldehyde level was approximately 12 μg/m³ (Meng and Wu 2015). Huang et al. measured the formaldehyde concentrations in the indoor air of 410 dwellings and 451 offices in Beijing in 2013; the results showed that indoor formaldehyde concentrations were higher than the Office of Environmental Health Hazard Assessment (OEHHA)-recommended acute reference exposure level (REL) in 85% of dwellings and 67% of offices (Huang et al. 2013).

The emission rates of formaldehyde from building materials are influenced by the surrounding air temperature and humidity (Huang et al. 2017). As described by many studies (Andersen et al. 1975; Crawford and Lungu 2011; Lin et al. 2009; Myers 1985; Parthasarathy et al. 2011), the emission rate of formaldehyde is positively related to both temperature and humidity (Huang et al. 2015; Xiong and Zhang 2010) and negatively correlated with ventilation rate (Hult et al. 2015; Liu et al. 2015; Salthammer et al. 1995). Huang et al. investigated and analyzed factors affecting the concentration of indoor formaldehyde in urban areas in 39 cities in southern and northern China. Their results showed that the concentration of winter indoor formaldehyde in northern cities is approximately 4.0-fold higher than that in southern cities. The reason is mainly the different living habits between the northern and southern people adapting to the climate (Huang et al. 2022). Coal is widely used for heating and cooking activities in rural households, and inefficient household stoves release a range of gaseous pollutants, especially in incomplete combustion (Qin et al. 2023). To keep warm, a central heating system is usually used, and the doors and windows are closed in northern China in winter. Thus, the ventilation is worse and the temperature is higher in rooms in the north than in those in the south. As indoor air purification has received more attention, Wang et al. provided data and theoretical support for microalgae to purify indoor air pollutants, including formaldehyde (Wang et al. 2023). According to Salthammer et al. (2013), the future ventilation strategy may be regulated because levels of formaldehyde in ambient (outdoor) air have been increasing with time.

3.1.2 Indoor Office Exposure

According to the Air Pollution Exposure Distributions of Adult Urban Populations in Europe (EXPOLIS) study in Helsinki, the average level of formaldehyde in the workplace was 15 μg/m³ (Rotko 2000). Formaldehyde concentrations in offices or public buildings varied from 3 to 33 μg/m³, detected from 2001 to 2006 at offices in southern Finland (Salonen et al. 2009). However, formaldehyde exposure in office seems more serious in developing countries. A study showed that the average formaldehyde concentration in 351 offices in China (data from 1996 to 2005) was 256 ± 2.7 μg/m³, which was similar to that in recently refurbished dwellings (Mui et al. 2008). In developed countries, environmentally friendly materials and better occupational health and safety (OHS) systems are used to protect their employees, while in developing countries, cost remains the first priority, and office air pollution remains a serious problem. A recent study showed that the volatile organic compound (VOC) patterns in the environment varied in offices, schools, kindergartens, and healthcare offices, probably reflecting the differences in typical activities and the use of materials, including formaldehyde. However, the authors did not expect those differences to be relevant to health outcomes (Wallenius et al. 2022).

3.1.3 Indoor Public Exposure

Although indoor public exposure has received attention from most countries, this problem still needs much work to be resolved. Some developing countries, due to their rapid urbanization, use massive volumes of unproven/unrated building materials for fast-track construction, which are frequent sources of formaldehyde and VOC emissions (Niculita-Hirzel 2022). For public transport, both urban and rural Formaldehyde (HCHO) emissions from cabin seats have an important impact on airborne HCHO pollution inside vehicle cabins (Qin et al. 2020). For 2003–2008, Italian scientists monitored formaldehyde in European public buildings for children such as schools and kindergartens. The results showed that in schools/kindergartens, the concentration of formaldehyde was 17.4 μg/m³, with a range of 1.5–49.7 μg/m³ (Kotzias et al. 2009). The indoor air quality was evaluated in classrooms in Germany during 2004–2005, which showed that indoor formaldehyde concentrations varied from 3.1 to 46.1 μg/m³ (Fromme et al. 2008). Data from Japan showed that formaldehyde concentrations were approximately 14 μg/m³ in winter and 30 μg/m³ in summer, as measured in 50 Japanese schools in 2000 (Uchiyama 2008). Bradman measured air samples in 2010–2011 from 40 early childhood education (ECE) facilities serving children <6 years old in California; the data showed that the median indoor formaldehyde level (μg/m³) was 17.8, while the maximum was 48.8 (Bradman et al. 2017). Compared to formaldehyde-free hair treatments, products with a high concentration of formaldehyde (1.7 and 9.3%) disperse this compound to the environment at a high and hazardous concentration, which is detrimental to both consumers and hair professionals (Henault et al. 2021). All the results showed that public indoor formaldehyde exposure is a serious problem worldwide.

3.1.4 Indoor Occupational Exposure

In some workplaces, formaldehyde is excessively used or produced, and staff are exposed to higher concentrations of formaldehyde (Mirabelli et al. 2011). For example, factories produce chemicals that are degraded into formaldehyde, including the production of formaldehyde itself. Occupational exposure to formaldehyde involves not only individuals employed in the direct manufacture of products containing certain levels of formaldehyde but also those actively utilizing such products (e.g., construction and decoration). Formaldehyde exposure occurs primarily by breathing air polluted by formaldehyde or by absorbing liquids containing formaldehyde through the skin (d’Ettorre et al. 2017; Lee et al. 2017; Peters et al. 2017; Adamović et al. 2021). People working in certain job sectors (e.g., manufacturers of resins, plywood and particle board, laboratory faculties, certain healthcare professionals, fire fighters, and mortuary employees) are exposed to higher levels of formaldehyde.

For the group with occupational contact with formaldehyde, protection is compulsory. In the medical area, 37% formaldehyde solution (i.e., formalin) is a preservative for dead bodies to prevent them from decaying (Tiruneh 2021; Zdilla 2021). Cadavers are usually preserved in an embalming solution composed of formaldehyde (Zhang et al. 2020). The level of formaldehyde in an anatomy lab was much higher than in many other environments. Medical students and instructors face a higher risk of inhalation exposure to formaldehyde from cadavers during dissection (Zdilla 2021). The indoor air and personal air samples in the breathing zone were collected in anatomy dissection classes in 2014 with sorbent tubes and analyzed by high-performance liquid chromatography (HPLC). The results showed that the concentration of formaldehyde was 140–498 μg/m³ in the indoor air and 151.2–1411.2 μg/m³ in the breathing zone of students and instructors. All personal exposure data exceeded the threshold limit of the National Institute for Occupational Safety and Health (NIOSH) and the World Health Organization (WHO) agencies (Kimbell et al. 2001; Saowakon et al. 2015). Considering the existence of clinical symptoms when the participants were exposed to 62.5 μg/m³ formaldehyde, a better ventilation system should be facilitated and furnished to protect staff and instructors in anatomy departments. The safety of anatomy pathology workers who are currently exposed to formaldehyde is still a matter of concern (d’Ettorre, et al. 2017).

Domingo et al. investigated formaldehyde concentrations in 15 Chinese medicine clinics (CMCs) with frequent use of moxibustion. The results showed that the mean values of formaldehyde in the CMCs’ indoor air were 654 μg/m³ and 155 μg/m³ in the therapy rooms and the waiting rooms, respectively. The high concentration of formaldehyde is a significant threat to the health of medical staff and patients’ health when applying moxibustion in CMCs (Domingo et al. 2014; Ladeira et al. 2010; Ochs et al. 2011; Viegas et al. 2013).

A study carried out in Portugal showed a positive correlation between occupational formaldehyde exposure time (years of exposure) and micronucleus frequency in peripheral blood lymphocytes (r = 0.401; p < 0.001) and in epithelial cells (r = 0.209; p < 0.01) (Viegas et al. 2013). The elevated risk value for occupational formaldehyde exposure suggested that the negative health impact for a certain group of people represented valid concern, and precautions should be taken to protect people from that risk (Ho et al. 2013; Wang et al. 2020a, b; Wolkoff 2020). More detailed information on indoor air exposure assessment for formaldehyde and health protection can be found in the United States Environmental Protection Agency (2024).

3.2 Outdoor Air Exposure

In general, outdoor formaldehyde pollution is less serious than indoor pollution since ambient levels are generally low, typically approximately 1–4 μg/m³. The human exposure characterization of chemical substances (HEXPOC) report showed that the ambient concentrations of formaldehyde are 1.5–16.4 μg/m³ with a medium value of 7.2 μg/m³ with data collected from Germany, Italy, the Netherlands, Brazil, Canada, Mexico, and the United States. Currently, residential building materials are regarded as an important source of ambient formaldehyde in mainland China. This study may be helpful to evaluate exposure to ambient formaldehyde and assist in making policies to protect the air quality and public health of the Chinese (Huang et al. 2022). The indoor–outdoor ratio is always far above 1 (Bruinen de Bruin et al. 2008; Institute for Health and Consumer Protection 2005). That is, normal air is safe unless the air is polluted. Although outdoor formaldehyde pollution was not recognized as severe by the public, Ban et al. found that mortality risks in nonaccidental, circulatory, and respiratory diseases increased by 0.36%, 0.36%, and 0.41%, respectively (Ban et al. 2022). Marcon et al. showed that children living near the largest chipboard manufacturing district had the highest average exposure to formaldehyde.

4 Dietary Exposure to Formaldehyde

Formaldehyde is also a natural ingredient in a variety of fruits, vegetables, meat, milk products, and fish (Jurvelin et al. 2001). The study by Bruinen et al. provides data on formaldehyde content in fruits and vegetables (Bruinen de Bruin et al. 2008). The concentration of formaldehyde in solid food and liquid drink listed was reviewed by IHCP (Institute for Health and Consumer Protection, 2005). Food and drink exposure varied, and the high concentration exposure was as high as 41,900 μg per day or as low as 4350 μg per day depending on the dietary habits of people (Hernandes 2020; Karolina 2019). However, whether formaldehyde is naturally present, or an adulterant is controversial. Human exposure to formaldehyde was calculated with the most represented food in the Bangladeshi diet. On the other hand, illegal usage of formaldehyde and ammonia by fishermen and fish sellers for longer preservation of fish and other seafood during sales and transportation has recently become a problem (Devaraj et al. 2021). An in vivo toxicity investigation indicated a time-dependent increase in blood formaldehyde levels in rats after they were fed formaldehyde-contaminated fish (23.3 mg/kg) for seven days (Kundu et al. 2020). Prolonged consumption of formaldehyde-preserved carps has an adverse health risk in the population. D-Ribose has been used as a nutrient and energetic supplement (Xue et al. 2022). In an in vitro experiment, Wang et al. observed that D-ribose water solution can spontaneously decompose and produce a certain amount of formaldehyde (Wang et al. 2019).

The average formaldehyde uptake per person in solid food is 14.3–50.5 μg/kg, 24–436 μg/kg, and 0.52–50.5 μg/kg in meat and poultry, fruit and vegetables, and fish and shellfish, respectively (Institute for Health and Consumer Protection, 2005). Formaldehyde uptake for people through a liquid diet as drinking water is less than 0.1 μg/kg, alcoholic beverages 0.08–15 μg/kg, coffee 14–65 μg/kg, and carbonated soft drinks (cola) 15–18 μg/kg (Institute for Health and Consumer Protection, 2005). For an adult with an average weight of 64 kg, the average formaldehyde intake was estimated to be 7.01 mg/kg of food or 0.12 mg/kg body weight per day (European Food Safety Authority 2014). This level of exposure to formaldehyde from the average diet in adults is lower than the maximum limits suggested by the European Food Safety Authority (EFSA) (<100 mg/kg food per day) and 11 mg/kg food per person per day (Wahed et al. 2016). There seems to be no health-associated risk when consuming food with traces of formaldehyde.

5 Formaldehyde Exposure and Health Problems

5.1 Acute Toxic

Inhaled formaldehyde presents acute toxicity on the respiratory tract, central nervous system, skin and eye, as well as chronic toxicity on the respiratory tract, particularly on pulmonary function (Solomons and Cochrane 1984). Acute exposure to formaldehyde can cause various health-related issues, such as irritation to various body parts (eye, nose, throat, and skin) (Agency for Toxic Substances and Disease Registry 1999; Dreyfuss 2010). Hundreds of people accidentally drank adulterated alcohol containing a high concentration (36.1%) of methanol in China on February 26, 1998 (Chi and Wu 1998). The first Central Nervous System (CNS) symptom of the victims was eye impairment, which was strikingly visible because of the acute toxicosis of the metabolic intermediate products of formaldehyde and formic acid from methanol (Casanova-Schmitz 1984a, b). Local acidosis resulting from formic acid accumulation impairs CNS cells, especially in acute toxicosis with high concentrations of methanol and formaldehyde (Bruckner and Warren 2001). Regarding the genotoxic effect, the sublethal concentrations of formalin showed a positive correlation with micronuclei according to the increase in its concentration independent of the time of exposure (Resendes et al. 2018).

5.2 Impairment and Symptoms of Intoxication

Azari et al.’s study showed a relationship between the concentration of indoor formaldehyde and the symptoms of the participants (Azari et al. 2012). In their study, the general indoor concentration of formaldehyde was measured as 62.5 μg/m³ in a school library. They found that the prevalence of symptoms due to formaldehyde exposure was greater in study groups than in controls. Under these conditions, the most commonly reported complaints included unpleasant odor (68%), cough (64%), sore throat and runny nose (56%), nasal irritation and itching (52%), and eye irritation (48%). Moreover, sustained exposure can lead to certain types of cancers (e.g., nasopharyngeal) and asthma (Kim et al. 2011). Formaldehyde is also classified as a human carcinogen that possibly leads to nasopharyngeal cancer and probably leukemia and is especially linked to sick building syndrome and multiple chemical sensitivities (Coggon et al. 2014).

In addition, smoking significantly increases indoor formaldehyde levels, and thus smoking cessation should be highly encouraged both in the workplace and at home. Li et al. studied the relationship between occupational exposure to formaldehyde and genetic damage in the peripheral blood lymphocytes of plywood workers. The results showed a dose–response relationship between formaldehyde exposure levels and double-stranded DNA breaks as well as chromosome damage in the peripheral blood of lymphocytes of plywood workers (Lin et al. 2013). Siew et al. showed that occupational exposure to formaldehyde increases the risk of nasal cancer but not nasopharyngeal or lung cancer (Siew et al. 2012). Zhang et al. examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls); they found that among exposed workers, peripheral blood cell counts were significantly reduced in a manner consistent with toxic effects on the bone marrow, and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells (Roberts et al. 2016; Zhang et al. 2010b; Kang et al. 2021). In addition, there were associations between exposure to formaldehyde and asthma diagnosis and asthma symptoms in both children and adults (Lam et al. 2021).

Concerns about these adverse effects have attracted public attention. A decade has passed since formaldehyde was classified as a known human carcinogen by the International Agency for Research on Cancer (World Health Organization 2010). As described by Han et al., the filter media had a crucial role in the performance of formaldehyde abatement (Han et al. 2017). Their work represents a breakthrough in providing experimental clues and key parameters for developing and adopting an effective catalytic oxidation filter for indoor hazard abatement, including formaldehyde.

5.3 Formaldehyde Toxicity to Human Body

Formaldehyde is an active carbonyl species with strong reducing properties, which enables the cross-linking reaction with DNA or proteins (Hoffman et al. 2015). People who stay in an environment with excessive indoor formaldehyde will suffer many health problems. Formaldehyde in vivo is accommodated and transported by lysosomes, induces oxidative stress (Evans et al. 2016; He et al. 2010), and is harmful to the human central nervous system, leading to cognitive impairment (Chen et al. 2017; Hu et al. 2016). Children under the age of 16 are more sensitive to higher concentrations of formaldehyde, asthma, and other respiratory system disorders and even leukemia (Yao et al. 2015; Zhai et al. 2013; Zhang et al. 2010a). The concentration and exposure time are critical factors in assessing the risk of formaldehyde on human health. Generally, a low concentration of formaldehyde has no obvious effects on the organism, but either long-term or high-concentration formaldehyde exposure will result in lesions to the eye, skin, respiratory tract, blood system, reproductive system, immune system, or even central nervous system to varying degrees (Bhat et al. 2024; Boothe et al. 2024; Duong et al. 2011; Tang et al. 2009).

6 Formaldehyde in Biological Evolution and Metabolism

Kalapos believes that formaldehyde is a component that has a role in life evolutionary processes (Kalapos 1998). He hypothesized that the (methyl) glyoxalase path might have bridged the early stage of evolution between formose and archaic reductive citric acid cycles (Kalapos 1999). For instance, formaldehyde acts as one of the intermediate products in the Miller–Urey experiment, which implied that reactions of formaldehyde in primaeval aquatic environments could be involved in the abiotic synthesis of complex organic molecules for the origin of life (Hill and Nuth 2003). As described by Roscoe and Miller, a CH₄ and CO mixture efficiently produced HCN and H₂CO (Stribling and Miller 1987). Gaseous molecules excited by electric discharge led to the production of organic compounds, including amino acids (Parker et al. 2014). In addition, exposure to pollutants was associated with genotoxic markers in exfoliated buccal cells (Marcon et al. 2014).

Furthermore, formaldehyde also functions as an energy source in some yeast and bacteria, although it is cytotoxic (Müller and Babel 1991). From prokaryotic to eukaryotic organisms, formaldehyde plays a role in the methylation and demethylation of DNA (Crider et al. 2012; Yan and Fujimori 2011), histones (Li and He 2016; Shi et al. 2004), and RNA (Gerken et al. 2007; Su et al. 2015). Li and He’s study showed (Li and He 2016) the life span of Drosophila showed a formaldehyde concentration-dependent manner when the flies were fed food containing formaldehyde. Low formaldehyde concentrations (0.037%) significantly prolonged the lifespan of female Drosophila, and higher concentrations (0.185%) shortened the lifespan of female and male Drosophila (Li et al. 2014, 2021). These discoveries demonstrate the importance of formaldehyde in biological processes (see Chaps. 2 and 3).

7 Conclusion

Formaldehyde can be detected universally, from air to food and in single cells. It will be generated by chemical synthesis or by biological metabolism. The wide usage of formaldehyde-containing products has caused severe formaldehyde pollution and a series of health issues, such as cancer, asthma, and neurological disorders. Outdoor formaldehyde levels are usually low, far lower than the toxic dosage set up by national standards, unless in a factory area with dramatic emission of formaldehyde. Indoor (including residential, office, and public places) formaldehyde pollution is the main concern for human health, especially formaldehyde emitted from construction and decoration materials, furniture, and textiles. Occupational formaldehyde pollution is still a major risk for employees working in factories or medical-related laboratories. Since indoor chemical pollutant studies are limited, more comprehensive studies on indoor air quality in day-care centers are needed globally (Anake and Nnamani 2023). The availability of low-cost sensors and mobile analytical equipment should also be studied and produced for affordable ground-level data accessibility. Protection equipment and well-ventilated facilities are necessary. To circumvent the health issues caused by formaldehyde, it is crucial to control the sources and remove formaldehyde, especially indoors.

Acknowledgments

This project was supported by grants from the National Natural Science Foundation of China (NSFC 81274093, 81871892), Shandong Province Natural Science Foundation (ZR2020MH056), and Health Department of Shandong Province (2019WS243, 202102040075), besides the grants listed in the Preface of this book.

Competing Financial Interest

The authors declare no competing financial interest.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_2

2. Metabolism of Formaldehyde In Vivo

Rong Xiao¹ and Rongqiao He2  

(1)

School of Life Sciences, Liaoning Normal University, Dalian, Liaoning, China

(2)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Dysmetabolism of formaldehyde shows a positive relationship with age-related cognitive impairment for approximately 30–40% of Alzheimer’s disease (AD) patients who have high levels of urine formaldehyde (see Chap. 9). To have a clear explanation, we divide the cellular formaldehyde pathways into two parts: “formaldehyde coming (synthesis or production)” and “formaldehyde going (process or degradation).” The metabolic homeostasis of formaldehyde is maintained between the “coming” and “going” pathways under the physiological state. In fact, formaldehyde comes from multiple pathways related to many compounds, such as sugars, lipids, amino acids, proteins, and nucleic acids, as well as some small molecules, and goes away in a relatively narrow metabolic lane. In addition, it also participates in other pathways, for instance, as a donor to modify histones, RNA, and DNA. Either “coming” or “going” metabolism dysfunctions would lead to an increase or decrease in endogenous formaldehyde. As described in Chap. 8, an imbalance (lack or excess) in formaldehyde metabolism induces a decline in learning and memory in Drosophila and rodents. It is known that the intestinal microbiota is involved in the metabolism of endogenous formaldehyde, and we discuss this topic in detail in Chap. 7. In this section, we discuss the characteristics of endogenous formaldehyde metabolism and summarize the pathways that are responsible for the generation and clearance of endogenous formaldehyde. To prevent excess formaldehyde accumulation, effective strategies, including modulators and medical devices that could target enzymes during the metabolism of formaldehyde, are also reviewed.

Keywords

FormaldehydeGenerationMetabolismLysosomeFormaldehyde dehydrogenase

Abbreviations

A

AD

Alzheimer’s disease

ADH

Alcohol dehydrogenase

ADH1

Alcohol dehydrogenase 1

ADH3

Alcohol dehydrogenase 3

ADH5

Alcohol dehydrogenase 5

Aβ

Amyloid-beta protein

ALA

Alpha lipoic acid

ALDH2

Aldehyde dehydrogenase 2

AMI

Acute myocardial infarction

AODs

Alcohol oxidases

ATP

Adenosine triphosphate

B

BSA

Bull serum albumin

C

CNS

Central nervous system

C. salexigens

Chromohalobacter salexigens

CO₂

Carbon dioxide

CoQ10

Coenzyme Q10

CSF

Cerebrospinal fluid

D

DAS

Dihydroxyacetone synthase

DEAE

Diethylaminoethyl

DMNA

N,N′-dimethyl-4-nitrosoaniline

DNPH

Dinitrophenylhydrazine

DPCs

DNA-protein cross-links

E

EDTA

Ethylenediaminetetraacetic acid

E. coli

Escherichia coli

ESD

Esterase D

F

FAD

Flavin adenine dinucleotide

FAE

Formaldehyde-activating enzyme

FDH

Formaldehyde dehydrogenase

FTO

Fat mass and obesity-associated protein

G

GSH

Glutathione

GSHPx

GSH peroxidase

GSHRx

GSH reductase

GSHST

GSH S-transferase

GSNOR

S-Nitrosoglutathione reductase

GSSG

Oxidized GSH disulfide form

H

H₂O₂

Hydrogen peroxide

H₄MPT

Tetrahydromethanopterin

HPLC

High-performance liquid chromatography

HPS

3-Hexulose-6-phosphate synthase

HU

Hindlimb unloading

K

KDMs

Lysine demethylases

L

LC/MS

Liquid chromatography and electrospray ionization mass spectrometry

LED

Light-emitting diode

LSD-1

Lysine-specific demethylase 1

LTP

Long-term potentiation

M

MAO-A

Type A monoamine oxidase

MDA

Malondialdehyde

MDHs

Methanol dehydrogenases

MDOs

Methanol: N,N’-dimethyl-4-nitrosoaniline oxidoreductases

M. extorquens AM1

Methylobacterium extorquens AM1

MGL

Methionine γ-lyase

MMSE

Mini-Mental State Examination

Mno

NDMA-dependent methanol oxidase/dehydrogenase

MODs

Methanol oxidases

MPO

Myeloperoxidase

M. smegmatis

Mycobacterium smegmatis

MTO

Methanethiol oxidase

MySH

Mycothiol

N

NAD

Nicotinamide adenine dinucleotide

NADPH

Nicotinamide adenine dinucleotide phosphate

NDMA

N, N-dimethyl-p-nitrosoaniline

NMDA

N-methyl-D-aspartate

NMR

Nuclear magnetic resonance

P

PD

Parkinson’s disease

PHI

6-Phospho-3-hexuloisomerase

PQQ

Pyrroloquinoline quinone

R

RL

Red light

RLT

Red-light treatment

ROS

Reactive oxygen species

RuBisCO

Ribulose-1,5-bisphosphate carboxylase/oxygenase

RuMP

Ribulose monophosphate

S

SAM

S-Adenosylmethionine

SAMP8

Senescence-accelerated mouse-prone 8 strain

SD

Sprague-Dawley

SELENBP1

Selenium-binding protein 1

SEMO-1

SELENBP1 ortholog with methanethiol oxidase activity

SHMT

Serine hydroxymethyltransferase

SSAO

Semicarbazide-sensitive amine oxidase

T

THF

Tetrahydrofolate

TMAO

Trimethylamine oxide

TMAO-ase

Trimethylamine oxide demethylase

T2DM

Type 2 Diabetes mellitus

V

VAP-1

Vascular adhesion protein-1

W

WISC

Wechsler Intelligence Scale for Children

X

XuMP

Xylulose-5-phosphate

1 Introduction

In the 1960s, Japanese scientists found that some of the trimethylamine oxide (TMAO) in the muscle of gadoids is converted into formaldehyde (HCOH) and dimethylamine when fish fillets are stored at temperatures above −25 °C (Amano and Yamada 1964a, b; Tokunaga 1964). More studies were carried out in the 1970s on the storage of fish meat under low temperatures concomitant with the production of endogenous formaldehyde, which resulted from TMAO (Castell et al. 1973; Tokunaga 1974). Sotelo et al.’s work demonstrates the production of endogenous formaldehyde from protein denaturation during frozen storage (Sotelo et al. 1995). Their work revealed that formaldehyde is produced and released in fish fillets during cell death and tissue degradation.

Endogenous formaldehyde comes from multiple metabolic pathways, such as denaturation of proteins (Sotelo et al. 1995), oxidation of lipids (Li et al. 2008), decomposition of reducing sugars (Wang et al. 2019), and oxidative stress (Yu 1990). Furthermore, formaldehyde is also produced from the metabolism of methanol (MeOH), methylamine, glycerol, sarcosine (N-methylglycine), dimethylaminoethanol, dimethylglycine, and other substrates that contain the CH₃N or CH₃O group. Demethylation of DNA, RNA, and histones is also considered a main way to generate formaldehyde in vivo (see Chap. 4). Recently, intestinal lengthening of mice from adulthood to agedness was observed (Mou et al. 2021). The intestinal flora has been proven to be involved in age-related cognitive impairment (Hu et al. 2016) and formaldehyde metabolism (Liu et al. 2017), involving the synthesis and degradation of formaldehyde (see Chap. 7).

In fact, all living things, including humans, produce and process formaldehyde at each moment all the time (The Environmental Protection Agency, USA “Toxicological Review of Formaldehyde Inhalation Assessment.” June 18, 2010). Although methanol is one of the original sources, the metabolism of formaldehyde in vivo is extremely complicated, and the pathways are diverse (Fig. 2.1) (Su et al. 2016; Tyihák et al. 1998; Burgos-Barragan et al. 2017). In this chapter, to review this complex topic, we discuss the metabolic pathways of formaldehyde by dividing the metabolic pathways into two aspects: “formaldehyde coming” and “formaldehyde going.” Either excess or lack of them will disturb the homeostasis of formaldehyde metabolism, which could lead to disorders of the central nervous system (CNS) and other systems.

Fig. 2.1

Pathways of formaldehyde generation and degradation. Endogenous formaldehyde comes from different pathways that are diverse and complex, which is referred to in He (2017). (Figure drawn by the authors)

2 Endogenous Formaldehyde Generation

Formaldehyde comes from various sources, such as the environment, food, intestines, compound degradation, and enzymatic catalysis. A series of enzymes are responsible for formaldehyde production (Table 2.1), including semicarbazide-sensitive amine oxidase (SSAO) (Boor et al. 1992; Yu et al. 1997), alcohol dehydrogenase 1 (ADH1) (MacAllister et al. 2011; Pocker and Li 1991), cytochrome P-450 enzymes (Clejan and Cederbaum 1991, 1992b; Megaraj et al. 2014), serine hydroxymethyltransferase (SHMT) (Renwick et al. 1998), trimethylamine oxide demethylase (TMAO-ase) (Gill and Paulson 1982), sarcosine dehydrogenase (Frisell and Mackenzie 1962; Porter et al. 1985), catalases (MacAllister et al. 2011; Slegers et al. 1984), myeloperoxidase (MPO) (Hazen et al. 1998), dimethylglycine dehydrogenase (Frisell and Mackenzie 1962; Porter et al. 1985), demethylases (lysine-specific demethylase 1, JmjC domain-containing proteins, AlkB family members, and hHR23A/B) (Aas et al. 2003; Burg et al. 2016; Chang et al. 2007; Jia et al. 2008; Shi et al. 2004; Trewick et al. 2002; Tsukada et al. 2006; Cao et al. 2020), and methanethiol oxidase (MTO) (Schild et al. 2014; Eyice et al. 2018; Pol et al. 2018; Philipp et al. 2021). Furthermore, methylotrophs usually use methanol dehydrogenases (MDHs) to convert methanol, which is their sole energy source, into formaldehyde (Vorholt 2002; Whitaker et al. 2015). Additionally, some microorganisms can produce BomA and BomB, which possess terminal oxygenase and ferredoxin reductase activities, to grow on glycine betaine and degrade it into dimethylglycine and formaldehyde (Shao et al. 2018).

Table 2.1

Enzymes for the generation and clearance of formaldehyde in vivo

Formaldehyde-producing enzyme

Superfamily

Substrate

References

Catalases

Methanol

MacAllister et al. (2011); Slegers et al. (1984)

ADH1

Dehydrogenases

Methanol

MacAllister et al. (2011); Pocker and Li (1991)

MDHs

Methanol

Whitaker et al. (2015)

MDOs

Methanol

Park et al. (2010)

BomA and BomB

Rieske nonheme iron oxygenase

Glycine betaine

Shao et al. (2018)

CYP4502E1

Cytochrome P-450 enzymes

Methanol, glycerol, and drugs

Clejan and Cederbaum (1991, 1992b); Megaraj et al. (2014)

SHMT

Serine

Renwick et al. (1998)

TMAO-ase

Lyases

TMAO

Gill and Paulson (1982)

Dimethylglycine dehydrogenase

Oxidoreductases

Dimethylglycine

Frisell and Mackenzie (1962); Porter et al. (1985)

Sarcosine dehydrogenase

Oxidoreductases

Sarcosine (N-methylglycine)

Frisell and Mackenzie (1962); Porter et al. (1985)

SSAO

Amine oxidases

Methylamine

Boor et al. (1992); Yu et al. (1997)

MPO

Peroxidases

Glycine

Hazen et al. (1998)

MTO

Selenium-binding protein

Methanethiol

Schild et al. (2014); Eyice et al. (2018); Pol et al. (2018); Philipp et al. (2021)

LSD-1 (KIAA0601 or KDM1A)

KDMs

Lysines in histones

Burg et al. (2016); Shi et al. (2004)

HR23A and HR23B

Lysines in histones

Cao et al. (2020)

Jmjc domain-containing proteins

KDMs

Lysines or arginines in histones

Chang et al. (2007); Tsukada et al. (2006)

AlkB (hABH or FTO)

AlkB

Methyl group in adenine, cytosine, uracil, and thymine of DNA and RNA

Aas et al. (2003); Jia et al. (2008); Trewick et al. (2002)

Formaldehyde-degrading enzyme

Superfamily

Product

References

ALDH2

Aldehyde dehydrogenases

Formic acid

Dicker and Cederbaum (1986); Dorokhov et al. (2015); MacAllister et al. (2011)

ADH3 (also named ADH5 or FDH)

Dehydrogenases

Formic acid

Koivusalo et al. (1989); MacAllister et al. (2011); Bae et al. (2017)

FAE

Methylene-H₄MPT

Goenrich et al. (2005)

HPS

D-arabino-3-hexulose-6-phosphate

Whitaker et al. (2015); Vartiainen et al. (2019)

DAS

Dihydroxyacetone and glyceraldehyde 3-phosphate

Yurimoto et al. (2011)

Abbreviations: ADH1 alcohol dehydrogenase 1, ADH3 alcohol dehydrogenase 3, ADH5 alcohol dehydrogenase 5, ALDH2 aldehyde dehydrogenase 2, DAS dihydroxyacetone synthase, FAE formaldehyde-activating enzyme, FDH formaldehyde dehydrogenase, FTO fat mass and obesity-associated protein, HPS 3-hexulose-6-phosphate synthase, H₄MPT tetrahydromethanopterin, KDMs lysine demethylases, LSD-1 lysine-specific demethylase 1, MDHs methanol dehydrogenases, MDOs methanol: N,N'-dimethyl-4-nitrosoaniline oxidoreductases, MPO myeloperoxidase, MTO methanethiol oxidase, SHMT serine hydroxymethyltransferase, SSAO semicarbazide-sensitive amine oxidase, TMAO trimethylamine oxide, TMAO-ase trimethylamine oxide demethylase

2.1 From Environment

Formaldehyde enters the respiratory system when individuals breathe polluted air that contains high levels of formaldehyde from various sources, such as vehicle exhaust, insecticides, insulation, embalming fluids, plywood adhesives, and abrasive materials (“Toxicological Review of Formaldehyde Inhalation Assessment” reported by Environmental Protection Agency, USA, June 18, 2010). Manufacturing plants and power plants are major sources of anthropogenic emissions of formaldehyde, which can generate or consume formaldehyde or materials that contain formaldehyde, including petroleum refineries, wood burning, coking operations, incineration, and tobacco smoke (see Chap. 1).

2.2 Methanol from Food

Methanol is the direct source of formaldehyde. Foods, including fruits, vegetables, and alcoholic beverages, can generate methanol in the healthy human body (Trézl et al. 1997; Burbacher et al. 1999). Usually, methanol is chemically locked to pectin from fruits and vegetables and can pass digestion without absorption by the gut. In 2014, Shindyapina et al. found that when human subjects consumed citrus pectin, ethanol, and red wine, the concentrations of methanol and formaldehyde in these volunteers’ blood plasma increased (Shindyapina et al. 2014). During heat and packaging processes, methanol is also released from fruits, vegetables, or other juices. Furthermore, fermentation of gut microbiota is also an important pathway to metabolize methanol into formaldehyde (Kostov et al. 1983). Although the human diet usually contains a very tiny component of methanol, humans began to take aspartame over the last 40 years, which would also be converted into methanol and might be associated with the increase in Alzheimer’ s disease (AD) incidence at the same time (Monte 2010). This might be attributed to gut esterases and peptidases, which metabolize aspartame into three common chemicals: aspartic acid, phenylalanine, and methanol (Choudhary and Devi 2015).

As early as 1953, Mackenzie et al. found that formaldehyde was isolated when methanol was incubated with an unfractionated liver homogenate (Mackenzie et al. 1953). With the combination of numerous studies, the detailed mechanism that accounts for the production of endogenous formaldehyde from methanol (CH₃OH) has been revealed in vivo. Although the physical and chemical properties of methanol are similar to those of alcohol, methanol is not suitable for drinking or inhalation due to the toxic products generated during its metabolism (Jacobsen and McMartin 1986; Pohanka 2016). Among the toxic products, the newly formed formaldehyde could lead to cytotoxicities or protein aggregations, which would finally cause cancer or AD. According to the summarization of previous studies, there are three main pathways that account for the generation of formaldehyde from methanol in vivo (Dorokhov et al. 2015; MacAllister et al. 2011). First, methanol in the presence of hydrogen peroxide (H₂O₂) could be oxidized to formaldehyde and H₂O by catalase (MacAllister et al. 2011; Slegers et al. 1984). During this reaction cycle, both the peroxidatic activities of catalase and hydroxyl radicals (•OH) generated from H₂O₂ are crucial for the oxidation of methanol (Cederbaum and Qureshi 1982). Second, methanol could be converted to hydroxyl radicals (•OH) by Fe²⁺ and H₂O₂. At the same time, hydroxyl radicals (•OH) are able to react with methanol, releasing formaldehyde and O₂ (MacAllister et al. 2011). Third, ADH1 can oxidize methanol to formaldehyde with the help of nicotinamide adenine dinucleotide (NAD⁺) (MacAllister et al. 2011; Pocker and Li 1991). In addition, cytochrome P-450 monooxygenase might also participate in the generation of formaldehyde (Guo et al. 2010; Wang et al. 2012). In vivo, endogenous methanol can be formed through the hydrolysis of carboxyl methyl esters, which are formed by the methylation of the -COOH group of amino acids in proteins with endogenous S-adenosylmethionine (SAM) as the methyl donor (Diliberto Jr and Axelrod 1976; Lee et al. 2008). The level of methanol, formaldehyde, or formic acid (HCO₂H) was increased when the striatal homogenates of male Sprague-Dawley (SD) rats were incubated with SAM (Lee et al. 2008). This indicates that endogenously formed methanol is one of the sources of formaldehyde in vivo.

In microorganisms, methylotrophs can use methanol, formaldehyde, or other one carbon atom as their sole energy source (Vorholt 2002; Whitaker et al. 2015). Among these methylotrophs, methanol dehydrogenases (MDHs) were proven to account for the conversion of methanol into formaldehyde (Whitaker et al. 2015). Previous studies have shown that there are mainly three kinds of MDHs, including pyrroloquinoline quinone (PQQ)-dependent MDHs, NAD-dependent MDHs, and oxygen-dependent methanol oxidases (MODs, also mentioned as alcohol oxidases, AODs), which are present in Gram⁻ bacteria, Gram⁺ bacteria, and yeasts, respectively (Whitaker et al. 2015; Vartiainen et al. 2019; Yurimoto et al. 2011). The active sites of PQQ-dependent MDHs such as XoxF-type MDHs and MxaFI MDHs are lanthanide and calcium, respectively. Although XoxF1 from Methylobacterium extorquens AM1 (M. extorquens AM1) was shown to oxidize both methanol and formaldehyde in vitro, XoxF1 only catalyzed methanol and generated formaldehyde in vivo, which requires a formaldehyde-activating enzyme (FAE) to couple formaldehyde in the tetrahydromethanopterin (H₄MPT) pathway to prevent formaldehyde accumulation (Goenrich et al. 2005; Good et al. 2019). Except for XoxF1, ExaF from the above strain was found to oxidize formaldehyde in vivo (Good et al. 2019). Recently, an N,N-dimethyl-p-nitrosoaniline (NDMA)-dependent methanol oxidase, also called NDMA-dependent methanol dehydrogenase (Mno), was identified from Mycobacterium smegmatis (M. smegmatis), which shares homology with other MDHs. The Mno can oxidize both methanol and formaldehyde, and play indispensable roles during the growth of M. smegmatis with methanol as the sole carbon source (Dubey et al. 2018; Dubey and Jain 2019a). In in vitro studies, the electron acceptor of this Mno, which requires nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor, is NDMA, whereas in in vivo studies, it is mycofactocin (Dubey and Jain 2019b). Similar to some properties of NAD-dependent MDHs, methanol: N,N′-dimethyl-4-nitrosoaniline (DMNA) oxidoreductases (MDOs) were also identified in some Gram⁺ bacteria, which could at least oxidize methanol and formaldehyde (Park et al. 2010). Some non-methylotrophic bacteria or yeasts can also oxidize methanol to formaldehyde by their alcohol dehydrogenases, although they are unable to use methanol as the sole carbon source to grow (Witthoff et al. 2013, 2015; Fernández et al. 2016; Vartiainen et al. 2019).

Generally, except for the glutathione (GSH)-dependent pathway that existed extensively, which we would mention in Sect. 3.2, the ribulose monophosphate (RuMP) pathway in prokaryotic methylotrophs would metabolize formaldehyde into fructose-6-phosphate through 3-hexulose-6-phosphate synthase (HPS) and 6-phospho-3-hexuloisomerase (PHI) in the presence of ribulose-5-phosphate (Whitaker et al. 2015; Vartiainen et al. 2019). For yeasts, formaldehyde generated by MODs is metabolized through dihydroxyacetone synthase (DAS) in the xylulose-5-phosphate (XuMP) pathway (Yurimoto et al. 2011; Whitaker et al. 2015; Vartiainen et al. 2019). The serine cycle is also responsible for formaldehyde assimilation in prokaryotic methylotrophs, similar to the processes in the one-carbon cycle and formaldehyde cycle (Vartiainen et al. 2019). H₄MPT, tetrahydrofolate (THF), bacillithiol, and mycothiol (MySH)-dependent formaldehyde dehydrogenases (FDHs) were also proven to be responsible for formaldehyde oxidation, except for GSH-dependent formaldehyde dehydrogenases (Vorholt 2002; Dubey et al. 2018). In addition, the ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO)-mediated Calvin cycle was also found to assimilate formaldehyde in some methylotrophic organisms (Dubey et al. 2018).

In 2018, Shao et al. found two novel enzymes, BomA and BomB, with terminal oxygenase and ferredoxin reductase activities, respectively, from Chromohalobacter salexigens (C. salexigens) DSM 3043. BomA, belonging to the Rieske nonheme iron oxygenase family, is able to cooperate with BomB in the presence of NADH, flavin, and oxygen and degrades glycine betaine to generate dimethylglycine and formaldehyde. The generated formaldehyde can also be assimilated since C. salexigens DSM 3043 contains genes encoding FDHs and formate dehydrogenases (Shao et al. 2018). Whether the formaldehyde generated from the above microorganisms affects the formaldehyde level in the human body needs further study.

2.3 Formaldehyde in the One-Carbon Cycle and in the Formaldehyde Cycle

Formaldehyde plays a role in the one-carbon cycle. One-carbon units in the form of methyl (−CH₃), methylene (−CH₂−), methenyl (−CH=), formyl (−CHO), and formimino (−CH = NH) groups can be transferred from one compound to another (Sun et al. 2011). This cycle provides cellular components, including proteins, lipids, and nucleic acids, for cell growth and proliferation (Locasale 2013). In vivo, the donors for one-carbon units are glycine, histidine, serine, tryptophan, and methionine. In the presence of THF, SHMT1 and SHMT2 catalyze serine to produce formaldehyde and glycine. Subsequently, formaldehyde reacts with THF to form 5,10-methylene-THF (Renwick et al. 1998; Burgos-Barragan et al. 2017). In the mitochondria, SHMT2 participates in the generation of 5,10-methylene-THF, while in the cytoplasm, SHMT1 is responsible for this reaction. Reversibly, 5,10-methylene-THF transfers a formaldehyde unit to glycine to generate serine and THF with the help of SHMT1 (Burgos-Barragan et al. 2017; Morellato et al. 2021). After oxidative degradation, THF and some folate derivatives are prone to release formaldehyde in vivo (Burgos-Barragan et al. 2017; Morellato et al. 2021). Actually, there are connections between the one-carbon cycle and formaldehyde cycle (Burgos-Barragan et al. 2017). Furthermore, plants might remove formaldehyde through C1 metabolism. As described by Zhang et al. petunia plants use ¹³C-labeled formaldehyde (2 mM) to synthesize [5-¹³C] methionine via C1 metabolism, probably in the cytoplasm (Zhang et al. 2014). When the concentrations of ¹³C formaldehyde increased to 4–6 mM, H¹³COOH and [2-¹³C] glycine were also generated in petunia plants through C1 metabolism, probably in chloroplasts and peroxisomes (Zhang et al. 2014). During this process, a small amount of [U-¹³C] glucose was generated via the Calvin cycle.

2.4 Formaldehyde from Biochemical Compounds

2.4.1 From Protein Denaturation

TMAO, whose chemical formula is (CH₃)₃NO, is composed of a small hydrophilic group (N⁺O⁻) and three methyl groups (Mondal et al. 2013). As early as 1956, it was first reported that TMAO could be reduced to trimethylamine, dimethylamine, and formaldehyde in a nonenzymatic process (Vaisey 1956). The microsomal fraction from skeletal muscle of red hake (Urophycis chuss) was able to reduce TMAO to dimethylamine and formaldehyde in the presence of Fe2+/3+ and either cysteine or ascorbate (Parkin and Hultin 1982). At the same time, an enzyme named TMAO-ase, which accounts for the reduction of TMAO to formaldehyde and dimethylamine, was purified from cod kidney (Gill and Paulson 1982). During this process, the generated formaldehyde was found to trigger protein denaturation in the fish muscle, which would finally result in the bad flavor, odor, and color of fish (Sotelo et al. 1995). Although TMAO is also known as a chemical chaperone that can help protein folding under denaturing conditions, the conversion of TMAO to formaldehyde causes TMAO to lose its protective properties (Tatzelt et al. 1996). Furthermore, the levels of TMAO, dimethylamine, trimethylamine, and formaldehyde were studied in 266 different types of fishes (Chung and Chan 2009). Regrettably, the reduction of TMAO to formaldehyde has not yet been reported in humans, and its relation to cognitive impairment has not yet been reported.

2.4.2 From Lipid Oxidation

During the oxidative degradation of polyunsaturated lipids, malondialdehyde (MDA) is released (Stancliffe et al. 2011). Thus, MDA is usually considered as a biomarker for oxidative stress (Del Rio et al. 2005). As one of the major products of lipid peroxidation, accumulation of MDA in vivo can be observed in many pathophysiological processes (Antus et al. 2014). In fact, patients with diabetes (Su and He 2014), cardiovascular diseases (Bagatini et al. 2011), and neurodegenerative disorders have higher concentrations of MDA in their blood (Sanyal et al. 2009). MDA, which acts as a reactive electrophile species, is cytotoxic, probably due to the two aldehyde groups. Therefore, tracing the changes in MDA and its products that result from proteins modified with MDA is conducive to understand their effects on oxidative stress and related diseases.

In 2008, Li et al. incubated N-acyl-4-sphingoine-1-phosphocholine (1 mg/mL myelin) with 50 mM phosphate buffer (pH 7.2) containing 1 mM H₂O₂ at 37 °C for 24 h. They measured formaldehyde with high-performance liquid chromatography (HPLC) coupled with dinitrophenylhydrazine (DNPH) absorption and observed the production of formaldehyde in the oxidation of myelin (Li et al. 2008) (Fig. 2.2). The reaction between 10 mM MDA and 0.05 mM calf serum albumin also produced formaldehyde. These data demonstrated that oxidation of cellular lipids can produce formaldehyde.

Fig. 2.2

Formation of formaldehyde from MDA and myelin oxidation. Formaldehyde is one of the products from decomposed MDA. Incubation of N-acyl-4-sphingoine-1-phosphocholine (1 mg/mL myelin) with 50 mM phosphate buffer (pH 7.2) containing 1 mM H₂O₂ at 37 °C for 24 h produces formaldehyde and MDA in the oxidation of myelin. (Source: Li et al. 2008)

2.4.3 From Reducing Sugar Decomposition

As described by Pinto et al. formaldehyde acts as a basic block for many compounds in organisms, for instance, the reducing sugar D-ribose (Pinto et al. 1980; Shapiro 1988). In the open-chain form, D-ribose has an active aldehyde group and constitutes the structural backbone of purines and pyrimidines (Shapiro 1988; Sutherland 2010). Usually, riboflavin and nucleic acids are the two major sources of D-ribose from the human diet. In healthy individuals, the concentration of D-ribose in the blood and the cerebrospinal fluid (CSF) is approximately 0.01–0.1 mM (Cai et al. 2005; Seuffer 1977). In vivo, the hexose monophosphate shunt and nucleotide metabolism could also generate endogenous D-ribose (Lager et al. 2003).

In 2013, Su et al. found abnormally high levels of D-ribose in the urine of type 2 diabetic patients compared with normal participants (Su et al. 2013). Three years later, Chen et al. demonstrated a high level of D-ribose in the blood of diabetic patients (Chen et al. 2016). These cases may support that diabetic patients suffer from dysmetabolism of not only glucose but also D-ribose. As shown in Fig. 2.3, formaldehyde can be produced from the decomposition of D-ribose (Wang et al. 2019). D-ribose is first decomposed into glyceraldehyde, followed by the production of formaldehyde under alkaline conditions. Yield of formaldehyde was also observed from D-ribose in the presence of lysine. Experiments on D-ribose incubated with glycine further demonstrated similar results. Intraperitoneal injection of D-ribose into C57BL/6 J mice increased the concentration of formaldehyde in the blood compared with the control. However, whether D-ribose can produce formaldehyde in vivo needs to be further investigated.

Fig. 2.3

Decomposition of D-ribose releases formaldehyde. (The figure was drawn by the authors and referred to authors’ work. Wang et al. 2019)

2.4.4 Formaldehyde from Dimethylaminoethanol, Dimethylglycine, and Sarcosine (N-Methylglycine)

In the 1950s, the formation of formaldehyde was observed during the oxidation reaction of dimethylaminoethanol, dimethylglycine, sarcosine (N-methylglycine), or methanol catalyzed by liver extractions without fraction (Johnston and Mackenzie 1956; Mackenzie et al. 1953). Later, mitochondria were found to be responsible for the formation of formaldehyde through the conversion of dimethylglycine or sarcosine (Mackenzie et al. 1953). After separation through diethylaminoethyl (DEAE)-cellulose and Ca₃(Po₄)₂-cellulose chromatography, Frisell and Mackenzie obtained purified dimethylglycine dehydrogenase and sarcosine dehydrogenase from mitochondria, which could act on the CH-NH group of dimethylglycine and sarcosine to generate formaldehyde, respectively (Frisell and Mackenzie 1962). Based on the enzymological characterizations, both dehydrogenases belong to the oxidoreductase family, which requires a flavin adenine dinucleotide (FAD) as a cofactor (Frisell and Mackenzie 1962). In the dimethylglycine dehydrogenase-catalyzed reaction, N,N-dimethylglycine, acceptor, and H₂O are converted to sarcosine, formaldehyde, and reduced acceptor (Porter et al. 1985). For the sarcosine dehydrogenase-catalyzed reaction, sarcosine, H₂O, and O₂ are converted to glycine, formaldehyde, and H₂O₂ with the help of FAD (Porter et al. 1985). Recently, spatial learning activity and long-term potentiation (LTP) were shown to be accompanied by the generation of formaldehyde in the hippocampus. Sarcosine dehydrogenase in the mitochondria accounts for the generation of formaldehyde in excited hippocampal neurons. Moderate formaldehyde generated by sarcosine dehydrogenase is helpful during spatial memory formation and LTP enhancement. In the sarcosinemia children who harbor sarcosine dehydrogenase mutation, the activity of sarcosine dehydrogenase in the blood, the level of formaldehyde in the urine, and the scores of the Wechsler Intelligence Scale for Children (WISC) were relatively lower than those of their healthy counterparts. Meanwhile, in sarcosine dehydrogenase gene knockout mice, the expression of sarcosine dehydrogenase as well as the levels of formaldehyde and sarcosine in the hippocampus were decreased significantly. These gene knockout mice exhibited poor spatial learning ability. In contrast, exogenous formaldehyde injection rescued the cognitive impairment induced by formaldehyde deficiency. Thus, sarcosine dehydrogenase is believed to be associated with cognition, probably by its ability to generate moderate formaldehyde, which further affects N-methyl-D-aspartate (NMDA) currents (Ai et al. 2019).

2.4.5 From Substrates Containing the CH₃N or CH₃O Group Mediated by the Cytochrome P-450 System

A great number of studies have shown that cytochrome P-450 in microsomes or mitochondria is closely related to formaldehyde liberation by glycerol oxidation. In 1988, Winters et al. observed that glycerol could be oxidized to a Nash-reactive material by rat liver microsomes in an NADPH-dependent manner (Winters et al. 1988). This Nash-reactive material was proven to be formaldehyde by the positive reaction of GSH-dependent formaldehyde dehydrogenase (Winters et al. 1988). Due to the inhibition of carbon monoxide on the glycerol oxidation reaction, the authors speculated that cytochrome P-450 might participate in this oxidative process (Winters et al. 1988). Two years later, the same authors used cytochrome P-450 isozyme inducers such as pyrazole, ethanol, or acetone to treat rats and then isolated their microsomes (Winters and Cederbaum 1990). When these microsomes were incubated with glycerol, the level of formaldehyde was increased, suggesting that glycerol might be an effective substrate for cytochrome P-450 (Winters and Cederbaum 1990). In the 1990s, the mechanism of glycerol oxidation mediated by cytochrome P-450 was gradually determined. The oxidation of glycerol catalyzed by microsomes or purified cytochrome P-450 (P4502E1) also requires the involvement of H₂O₂ and nonheme iron except NADPH (Clejan and Cederbaum 1991). During this reaction cycle, the authors hold that cytochrome P-450 catalyzes iron with H₂O₂ to generate an oxidant that could further metabolize glycerol to formaldehyde (Clejan and Cederbaum 1992a). Glycerol could be cleaved by the oxidant to form formaldehyde with breakage of a carbon–hydrogen bond (Rashba-Step et al. 1994). In addition to glycerol, vicinal diols such as 1,2-propanediol and 1,2-butanediol or charged glycol, for instance, alpha-glycerophosphate, could also liberate formaldehyde with the interaction of an oxidant derived from H₂O₂ plus nonheme iron (Clejan and Cederbaum 1992b). With a summary of the studies on cytochrome P-450-catalyzed formaldehyde generation, cytochrome P-450 was proven to act as a terminal oxidase in the electron transfer chains, which could participate in the demethylation process of a variety of substrates containing the CH₃N or CH₃O group (Kobayashi et al. 2000; Vaz et al. 1996). Recently, more than 21 cytochrome P-450 isoenzymes have been reported. Importantly, cytochrome P-450 could participate in the metabolism of various drugs and procarcinogens in vivo. During this process, formaldehyde could also be released. In 2014, Megaraj et al. showed that cytochrome P-450 enzymes, especially cytochrome P-450 2E1 in the microsomes of the liver and intestine, were responsible for catalyzing azoxymethane, which is a colon carcinogen, to produce formaldehyde in vivo (Megaraj et al. 2014). In this reaction, azoxymethane is hydroxylated to form methylazoxymethanol, which is subsequently converted into formaldehyde and a methyldiazonium ion (Megaraj et al. 2014).

2.5 Oxidative Stress Produces Formaldehyde

2.5.1 SSAO Catalyzes Methylamine to Generate Formaldehyde

SSAO is also known as a vascular adhesion protein-1 (VAP-1) and requires topaquinone as the cofactor (Jakobsson et al. 2005). In addition to blood plasma, SSAO is distributed in many cells, such as vascular smooth muscle cells, adipocytes, chondrocytes, and odontoblasts (Boomsma et al. 1997; Moldes et al. 1999; Filip et al. 2016; O’Sullivan et al. 2002). It is also localized in the cytoplasm of endothelial cells and at the outer membrane surface (Jaakkola et al. 1999). In recent decades, a great number of studies have shown that the expression level of SSAO is increased during pathological processes such as vascular disorders, chronic heart failure, diabetic complications, and AD (Boomsma et al. 1997; Obata 2006; Ullah et al. 2013; Yu 2001; Yu et al. 2003). Recently, changes in the expression and activity of SSAO were also observed during the microgravity simulation process (Zhang et al. 2012; Rcheulishvili et al. 2021; Yao et al. 2021). In 1992, SSAO was first reported to catalyze the deamination reaction of endogenous methylamine to produce toxic formaldehyde, H₂O₂, and ammonia (Boor et al. 1992). Therefore, the released formaldehyde may be a crucial factor leading to lesions in endothelial cells and plaques formed from aberrant protein aggregation (Obata 2006; Yu 2001; Yu et al. 2003; Yu and Zuo 1993).

In 1997, Yu et al. indicated that endogenous adrenaline is also an important source for the formation of formaldehyde in vivo (Yu et al. 1997). During stress conditions, adrenaline can be released into the circulatory system and deaminated by type A monoamine oxidase (MAO-A) to form 2-(3,4-dihydroxyphenyl)-2- hydroxyacetaldehyde, H₂O₂, and methylamine (Yu et al. 1997). Subsequently, the generated methylamine could be further converted to toxic formaldehyde, H₂O₂, and ammonia through deamination induced by SSAO, which is distributed in the cardiovascular smooth muscles and the circulatory system (Yu et al. 1997). The authors hold that the formed formaldehyde may be responsible for the initiation of endothelial injury (Yu et al. 1997). In 2004, Gubisne-Haberle et al. provided that the formaldehyde released from methylamine deamination, which is catalyzed by SSAO in human brain meninges, could effectively cause cross-linkage between formaldehyde and proteins (Gubisne-Haberle et al. 2004). In 2014, Qiang et al. showed that both formaldehyde and SSAO levels were significantly elevated in the brains of senescence-accelerated mouse-prone 8 strain (SAMP8) mice, which are classic AD models, at the age of three months compared with age-matched SAMR1 mice (Qiang et al. 2014). The authors speculated that the elevated levels of SSAO might account for the high concentration of formaldehyde in the brains of SAMP8 mice, which probably leads to Tau hyperphosphorylation and protein aggregation with cognitive impairment as an ultimate result (Qiang et al. 2014). Similarly, the formaldehyde content and SSAO activity were also increased in the brains of SAMP8 mice at the ages of five and seven months, respectively, compared with SAMR1 mice at the same age, which indicated that SSAO accounts for the generation of formaldehyde in vivo again (Zhang et al. 2019). In 2019, a medical device called LED-RL, which emits red light (RL; 630 nm) from a light-emitting diode (LED), was designed to treat SAMP8 mice at the ages of three and five months for two months (30 min per day and five days per week), respectively. After LED-RL treatment, SSAO activity was decreased to normal levels in the brains of five-month-old SAMP8 mice, but was not affected in seven-month-old SAMP8 mice. The authors hold that the SSAO activity affected by LED-RL exposure might be one of its reasons to improve cognitive impairment in SAMP8 mice (Zhang et al. 2019). Compared with the controls, the high level of formaldehyde in the blood and urine from the stroke, poststroke dementia, and AD patients was probably originated from the increased expression of SSAO in their blood. Furthermore, the expression level of SSAO was also high in the hippocampus from the dementia patient corpses, which might lead to the high level of formaldehyde in their hippocampus (Tong et al. 2017). In addition, acute high-altitude hypoxia treatment caused the accumulation of formaldehyde in the cerebrum of male C57BL/6 mice and increased the expression of SSAO, which finally resulted in neurological deficits. Nano-packed coenzyme Q10 (CoQ10) rescued neurological deficits by reducing cerebral formaldehyde and SSAO expression (Wang et al. 2022a). During the stress of hindlimb unloading (HU), the formaldehyde level increased in the fastigial nucleus of the cerebellum and gastrocnemius muscle in C57BL/6 mice in a time-dependent manner, without changes in their liver, kidney, and spleen. The authors hold that the elevated formaldehyde that could cause motor impairment in the HU-stress mice was partly induced by the increased expression and activity of SSAO in the cerebellum and serum. Treatments with 630 nm RL, CoQ10, and RL plus CoQ10 are three effective strategies proven to significantly prevent formaldehyde accumulation in the muscle and cerebellum of HU-stress mice by reducing the expression and activity of SSAO (Yao et al. 2021).

2.5.2 Formaldehyde from Glycine Oxidation Catalyzed by MPO

MPO is a heme peroxidase, which is expressed in neutrophils, monocytes, and macrophages (Bos et al. 1978; Daugherty et al. 1994; Klebanoff and Clark 1978). During the pathogen invasion process, activated neutrophils release MPO to produce hypohalous acids by reacting with H₂O₂ and halide at inflammatory sites (Kato 2016; Davies 2011). The generated hypohalous acids would account for much of the antibactericidal activity of neutrophils (Davies 2011). As early as 1968, Zgliczyński et al. revealed that MPO could catalyze not only the classic substrates for peroxidase but also α-amino acids, which provided clues for the study of aldehyde generation through the MPO–H₂O₂–chloride system (Zgliczyński et al. 1968). In the 1990s, many reports released that human neutrophils can employ this MPO–H₂O₂–Cl⁻ system to oxidize α-amino acids to reactive aldehydes (Anderson et al. 1997). Their structures were analyzed by a variety of mass spectrometric methods (Hazen et al. 1998). MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic (Vasilyev et al. 2005). Among the amino acid-derived aldehydes, formaldehyde is produced by oxidation of aliphatic glycine in the presence of MPO, H₂O₂, and Cl⁻ in vitro (Hazen et al. 1998). Those aldehyde derivatives, including formaldehyde, 2-hydroxyproprianaldehyde, and acrolein, were more cytotoxic than the other α-amino acid-derived aldehydes in HA1 fibroblast survival assays (Vasilyev et al. 2005). To determine whether amino acid-derived aldehydes are also formed in vivo, both wild-type and MPO−/− mice were used. After acute myocardial infarction (AMI) induction, aldehydes, including formaldehyde, in ventricular tissues of wild-type mice were generated significantly compared with those in MPO−/− mice (Vasilyev et al. 2005). That is, formaldehyde can be generated through the MPO–H₂O₂–chloride system in vivo. Gellhaar et al. observed significant increases in MPO-immunoreactive cells in brain regions affected by neurodegeneration in Parkinson’s disease (PD) and AD, supporting investigations of MPO inhibitors in novel treatment strategies (Gellhaar et al. 2017).

2.5.3 Formaldehyde from Methanethiol Catalyzed by MTO

Previously, many studies have shown that methanethiol (CH₃SH, called methylmercaptan) could be degraded into formaldehyde, hydrogen sulfide, and H₂O₂ by MTO in Thiobacillus, Rhodococcus, and Hyphomicrobium (Eyice et al. 2018). Biochemical analysis showed that MTO purified from Hyphomicrobium sp. VS is a homotetrameric enzyme requiring copper for its catalytic activity (Eyice et al. 2018). A recent study showed that MTO is widely distributed in bacteria and shares high identity with selenium-binding proteins from other Hyphomicrobium species (Eyice et al. 2018). According to the work of Pol et al. human selenium-binding protein 1 (SELENBP1) possesses MTO activity and can also metabolize methanethiol into formaldehyde, hydrogen sulfide, and H₂O₂ (Pol et al. 2018). Usually, reduced expression levels and mutations of SELENBP1 are observed in patients with tumors and halitosis, respectively (Pol et al. 2018). In humans, methionine, mainly ingested from the daily diet and degraded by the microbiome located in the colon, usually generates the MTO substrate methanethiol (Philipp et al. 2021). The conversion of methanethiol from methionine is due to an enzyme named methionine γ-lyase (MGL), which is originated from bacteria located in the intestine but is not present in humans (Philipp et al. 2021). Although Philipp et al. did not detect the generated formaldehyde in Caco-2 cells, they detected increases in two other products (hydrogen sulfide and H₂O₂) in differentiated Caco-2 cells, accompanied by the upregulation of SELENBP1 (Philipp et al. 2021). The above results indicated that MGL from bacteria generates methanethiol, which is further catalyzed by SELENBP1 in the intestine, as SELENBP1 possesses MTO activity (Philipp et al. 2021). Therefore, SELENBP1 is a novel enzyme that also provides formaldehyde in vivo. Another SELENBP1 ortholog with methanethiol oxidase activity (SEMO-1), which was also named Y37A1B.5, was identified in the nematode (Caenorhabditis elegans) (Philipp et al. 2022). Although the authors did not detect the products of formaldehyde and H₂O₂, which are usually generated from methanethiol degradation catalyzed by SEMO-1, the hydrogen sulfide product was also observed in wild-type worms but not in semo-1 knockout nematodes, suggesting that SEMO-1 possesses MTO activity and promotes the generation of formaldehyde from methanethiol degradation (Philipp et al. 2022). Interestingly, semo-1 knockout worms showed a longer lifespan and better tolerance to oxidative stress than wild-type worms. The authors speculated a clue to cause aging related to those products, including H₂O₂ and formaldehyde (Philipp et al. 2022). However, a similar phenomenon has not been observed in mammals, and further studies are still required in the future (Philipp et al. 2022).

2.5.4 Cells Produce Reactive Oxygen Species (ROS) in the Presence of Formaldehyde and Vice Versa

Breakthroughs in biochemistry have furthered our understanding of the onset and progression of various diseases, such as AD, and have advanced the development of new therapeutics (Evans et al. 2016; Umeno et al. 2017). Abnormally high levels of formaldehyde induce cellular oxidative stress, resulting in abnormal modification and accumulation of proteins, neuronal death, and cognitive impairment. As described by Jung et al. levels of intracellular ROS were elevated when the concentration of formaldehyde increased at the same time. Formaldehyde-induced ROS can be released from eosinophils after they migrate to the inflammatory sites of the airways (Jung et al. 2007). Recently, Chen et al. added formaldehyde to N2a cells and observed the yield of ROS. That is, formaldehyde is able to induce N2a cells to produce ROS by triggering cellular oxidative stress during culture (Chen et al. 2017). Furthermore, the carbonyl group of formaldehyde is active in the reaction with the thiol group of GSH, leading to an imbalance in the ratio between GSH and the oxidized GSH disulfide form (GSSG) and inducing oxidative stress (Umansky et al. 2022). Although the total GSH content was not altered when cerebellar granule neurons were treated with exogenous formaldehyde, the ratio of extracellular GSH to cellular GSH increased, suggesting that exogenous formaldehyde exposure could promote the export of GSH (Tulpule et al. 2013). The export of GSH from neurons and glial cells, including oligodendroglial OLN-93 cells, was proven with the help of Mrp1 (Tulpule et al. 2012, 2013). However, exposure to exogenous formaldehyde (0.5 mM) did not change the content of GSSG outside the cells or inside the cells or the activity of GSH peroxidase (GSHPx), GSH reductase (GSHRx), and catalase (Tulpule et al. 2013). Cellular GSH decline induced by 0.5 mM formaldehyde only slightly impaired the viability of neurons under oxidative stress, as the release of lactate dehydrogenase from neurons was not more than 15% compared to that of the controls. The above results indicated that neurons might have enough antioxidative strategies to protect themselves from oxidative stress after exogenous formaldehyde exposure (Tulpule et al. 2013).

To investigate excess formaldehyde induced by oxidative stress, which leads to neuronal death and cognitive dysfunction, a technique for monitoring the dynamic distribution of formaldehyde in living cells was performed by Chen et al. (2017). In the cellular experiment, they added H₂O₂ to bEed.3 cells and found that formaldehyde was produced and localized in the lysosomes, as detected by the formaldehyde molecular probe FAP-1. They added formaldehyde to the cells and observed that the formaldehyde signal markedly increased inside lysosomes and then decreased with time. Furthermore, they employed SD rats that were operated on with bilateral carotid occlusion and isolated lysosomes from rat brains. Then, formaldehyde was detected with the fluorescent probe. The results showed that formaldehyde was located in the lysosomes but not in the cytoplasm (Fig. 2.4). These results suggested that ROS are able to trigger the yield of formaldehyde in cells during oxidative stress (Chen et al. 2017). Based on a report from Zhang et al. the level of H₂O₂ was relatively higher in the brains of SAMP8 mice than that in those of SAMR1 mice. In turn, H₂O₂ was found to inhibit the activity of FDH, which is an important enzyme that degrades formaldehyde, and further caused formaldehyde accumulation in the brains of SAMP8 mice. In 2019, Zhang et al. tried to use a device named LED-RL to illuminate SAMP8 mice and found that both the levels of H₂O₂ and formaldehyde were decreased in the brains by its ability to increase the expression of FDH and catalase (an enzyme that degrades H₂O₂), as well as to restore their activities (Zhang et al. 2019).

Fig. 2.4

Formaldehyde levels in SD rats with bilateral carotid occlusion. Levels of formaldehyde (FA) in the lysosomes and cytoplasm of brain cells of SD rats (n = 12) that underwent bilateral carotid occlusion. Data are expressed as the mean ± standard deviation; **p < 0.01; ###p < 0.001. (Source: Chen et al. 2017)

During exposure to hydroxyl radical mediators, thiazolidine-4-carboxylic acid, which is also known as thioproline, was formed from the reaction of cysteine with the generated formaldehyde stimulated by the above oxidants in Escherichia coli (E. coli) cells (Liu and Chan 2015; Ham et al. 2020). Recently, thioproline, which is used as a dietary supplement, was found to protect HeLa cells from oxidative insults and improve cell viability, accompanied by the increasing ratio of GSH/GSSG (Ham et al. 2020). N-formyl-cysteine produced from thioproline oxidation in vivo was able to protect HeLa cells from oxidative stress. Similar to another supplement, N-acetyl-L-cysteine, thioproline exhibited antioxidant capability analogously, suggesting the possibility for thioproline to be used as a health-protecting supplement to disorders induced by oxidative stress (Ham et al. 2020). During protein synthesis, thioproline can replace proline (Liu et al. 2020). Thioproline-glycine was recently detected when GSH was reacted with formaldehyde, in addition to the products including S-hydroxymethyl GSH, which we would like to mention in Sect. 3.2, and (S)-1-(((R)-2-amino-3-(carboxymethylamino)-3-oxopropylthio)methyl)-5-oxopyrrolidine-2-carboxylic acid. Under physiological conditions, thioproline-glycine was also detected in human HepG2 cells even when the cells were not treated with exogenous formaldehyde, suggesting that endogenous formaldehyde generated in vivo accounts for the production of thioproline-glycine. Exogenous formaldehyde exposure or treatment with Fe²⁺-ethylenediaminetetraacetic acid (EDTA) (a hydroxyl radical mediator) resulted in a significant increase in thioproline-glycine in human HepG2 cells. As those data indicated, formaldehyde induced by oxidative stress in vivo reacts with GSH, resulting in the adduct thioproline-glycine. Stable thioproline-glycine with high abundance may act as a marker to assay formaldehyde exposure or oxidative stress in vivo (Pan et al. 2020).

From these three paragraphs, ROS are able to promote cellular oxidative stress and the production of formaldehyde (Chen et al. 2017). In contrast, formaldehyde also triggers oxidative stress and induces the production of ROS. Thus, ROS and formaldehyde may form a positive circle in the cells during oxidative stress, as shown in Fig. 2.5. Because lysosome is an important cellular organelle for endogenous formaldehyde (Xiong and Zhu 2016), we hypothesized here that endogenous formaldehyde could be used as a biomarker for lysosome function and dysfunction (He 2016).

Fig. 2.5

Circle of H₂O₂ and formaldehyde. The addition of H₂O₂ promotes oxidative stress in cells followed by the production of formaldehyde. Cells produce H₂O₂ in the presence of formaldehyde. (Source: Chen et al. 2017)

2.6 From Intestinal and Oral Flora

The microbiota–gut–brain axis is composed of neural, immune, endocrine, and metabolic pathways and is a bidirectional communication system. The gut microbiota, also called “the second brain,” can modulate brain function and regulate the pathogenesis of neurodegeneration, including age-related AD (Hu et al. 2016). It has been found that Salmonella enterica subsp. enterica serovar Typhimurium possesses the genes encoding MDHs (https://​www.​ncbi.​nlm.​nih.​gov/​protein). Furthermore, recent studies have shown that the gut microbiota is closely associated with host cognition, as well as AD-related pathogenesis (Jiang et al. 2017). It was reported that colonization of intrinsic pathogens is able to disturb the gut–brain axis, which finally causes inflammatory host responses and pathogen-mediated diseases (Stecher 2015). Furthermore, highly elevated levels of formaldehyde were observed in the cecum of transgenic APP+/PS1+ mice compared with age-matched wild-type C57BL/6 mice (Liu et al. 2017). These data suggest that the intestinal microbiota is involved in the metabolic pathways for endogenous formaldehyde in transgenic mouse models of AD (see Chap. 7).

In the oral cavity, Porphyromonas gingivalis, which is one of the pathogenic bacteria resulting in halitosis, can degrade methionine and form methylthiol, 2-ketobutyrate (alpha-ketobutyrate), and ammonia with the help of methionine gamma-lyase deaminase. Subsequently, an uncharacterized methylthiol oxidase catalyzes methylthiol into formaldehyde, H₂O₂, and H₂S (Kandalam et al. 2018). Regrettably, the characterization of this methylthiol oxidase and whether formaldehyde generated through this pathway affects its systematic level in the human body still need further study.

2.7 From Oxidative Demethylation

In live organisms, methylation is one of the most important modifications of histones and can regulate a variety of biological processes, including transcription activation and repression. To date, the methyl groups in the lysines of histones could be removed by KDMs, a family of enzymes including the flavin-dependent KDM1 enzymes, the 2-oxoglutarate- and oxygen-dependent JmjC KDMs (Burg et al. 2016; Chang et al. 2007; Shi et al. 2004; Tsukada et al. 2006). During these oxidative demethylation processes, formaldehyde could be released. In 2020, Cao et al. found two new histone demethylases named hHR23A and hHR23B that specifically demethylate histone H4K20 and produce formaldehyde in the presence of Fe(II), α-ketoglutarate, and ascorbic acid (Cao et al. 2020). In 2021, serine 8 and 26 in synthesized amyloid-beta protein (Aβ)42 monomers were found to generate formaldehyde through oxidative demethylation in vitro (Fei et al. 2021). Furthermore, the methyl group of the adenine as well as cytosine in DNA and RNA could also be demethylated by AlkB, hABH2, or FTO, concomitant with the production of formaldehyde (Aas et al. 2003; Jia et al. 2008; Trewick et al. 2002). In 2018, the accumulation of formaldehyde in the hippocampus of adult SD rats injected with high glucose was proven to occur through DNA demethylation (Tan et al. 2018). The detailed processes and mechanisms for the production of formaldehyde that resulted from the reaction of methylation and demethylation are discussed in Chap. 4.

3 Formaldehyde Metabolic Pathways

To date, a great number of studies have shown that formaldehyde is a carcinogenic molecule that causes a variety of serious diseases and even human death. Thus, scientific reports have recommended that we should try our best to avoid inhalation of toxic formaldehyde as much as possible. Even though we were successfully protected from the adverse effects induced by exogenous formaldehyde, endogenous formaldehyde could also be formed by a series of pathways, as mentioned above. How could endogenous formaldehyde be effectively metabolized? Fortunately, mitochondrial ALDH2 or GSH-dependent ADH3 (FDH or ADH5) was found to be in charge of the metabolism of endogenous formaldehyde in vivo (Table 2.1) (Koivusalo et al. 1989; Bae et al. 2017; Zhang et al. 2019). Furthermore, intestinal microbiota and tetrahydrofolic acid could also consume excess formaldehyde. However, formaldehyde reacts with biomacromolecules, including protein, DNA, and RNA, if it accumulates in excess.

3.1 Mitochondrial ALDH2 Pathway

In our daily lives, methanol from fruits, vegetables, fermented beverages, soft drinks, and aspartame-sweetened foods is usually metabolized by multiple reactions in vivo (Burbacher et al. 1999). As we have described above, ingested methanol at a low dose could be converted to formaldehyde through oxidation in three different pathways (Dorokhov et al. 2015; MacAllister et al. 2011). Noticeably, the generated formaldehyde could be further oxidized to formic acid catalyzed by ALDH2 in the presence of NAD⁺ (Dicker and Cederbaum 1986; Dorokhov et al. 2015; MacAllister et al. 2011). Under physiological conditions, formic acid is usually dissociated to release formate and hydrogen ions. Importantly, neurotoxic formate is converted to carbon dioxide (CO₂) in a THF-dependent multistep pathway (Noker and Tephly 1980). During this reaction cycle, formate could first bind to THF to form [¹⁰N] formyl-THF, which is catalyzed by 10-formyl-THF synthetase. Subsequently, NADP oxidoreductase catalyzes the oxidation of the formyl group on [¹⁰N] formyl-THF directly to release CO₂ (Brosnan et al. 2015).

Recently, a great number of studies have shown that the activity of ALDH2 is responsible for formaldehyde removal in vivo. In 2018, Tan et al. found that type 2 diabetes mellitus (T2DM) patients exhibited relatively lower ALDH2 activity and Mini-Mental State Examination (MMSE) scores but had higher levels of formaldehyde in their blood and urine than age-matched controls. In particular, T2DM patients with ALDH2 gene mutations exhibited higher levels of formaldehyde in their blood and urine than T2DM patients with normal ALDH2 gene expression. In addition, the formaldehyde level in the blood and hippocampus from ALDH2 knockout (ALDH2−/−) mice also increased, which showed cognitive impairment during the Morris water maze test. In contrast, human ALDH2+/+ Tg mice that overexpress ALDH2 exhibited decreased formaldehyde levels in their hippocampus and improved cognitive decline (Tan et al. 2018). In addition, an antitumor agent named disulfiram, which is also known as an inhibitor of ALDH2, resulted in formaldehyde accumulation in cancer cells and led to their death by disrupting the clearance pathway of formaldehyde (Komarova et al. 2019). Similarly, the formaldehyde detoxifying activity significantly decreased in the mitochondria from the liver extracts of the Aldh2−/− mice. The mean concentrations of blood formaldehyde in wild-type, Aldh2−/−, Adh5−/⁻ and Aldh2−/−Adh5−/− mice were approximately 4 μM, 9 μM, 11 μM, and 44 μM, respectively (Dingler et al. 2020). Thus, both mitochondrial ALDH2 and cytosolic ADH5 account for the elimination of formaldehyde in vivo. Compared with their healthy counterparts, AD patients suffered from lower blood ALDH2 activity, which may be one of the causes of excess endogenous formaldehyde and dementia. Among these AD patients, the genotypes of ALDH2 were homozygote ALDH21*1 (GG), heterozygote ALDH21*2 (GA), and homozygous mutant ALDH22*2 (AA). More importantly, the hALDH22*2 (AA) mutation does not possess ALDH2 activity. Therefore, ALDH2 acts as a major enzyme to remove excess formaldehyde in vivo, and enzymatic inactivation may be related to cognitive impairment (Ai et al. 2019). After treatment with acute high-altitude hypoxia, the expression and activity of ALDH2 in male C57BL/6 mice, which exhibited poor learning and memory abilities, were reduced and were responsible for the accumulation of formaldehyde in the brain when compared with control mice (Wang et al. 2022a). The above data further demonstrated the important role of ALDH2 in formaldehyde metabolism.

Since ALDH2 was recognized as a major metabolic enzyme that removes excess formaldehyde in vivo, some studies have tried to enhance the activity of ALDH2 to improve cognitive dysfunction induced by accumulated formaldehyde. For example, alpha lipoic acid (ALA; 1,2-dithiolane-3-pentanoic acid) is a kind of nutraceutical and might be used to prevent AD occurrence and treat AD patients. Both ALA and Alda-1 (an activator of ALDH2) decreased formaldehyde in the blood of female nonpregnant Balb/c mice (Shindyapina et al. 2017). ALA can decrease the formaldehyde level in mice probably by increasing the expression and activity of ALDH2 in the brain, but not due to its antioxidative ability (Shindyapina et al. 2017). Alda-1 functions in decreasing the formaldehyde level in neurovascular cells and alleviates impairment during AD progression by activating ALDH2 (Tao et al. 2022).

Studies on formaldehyde scavengers, such as L-cysteine, CoQ10, and silibinin, have been continued in recent years. L-cysteine was observed to remove formaldehyde in the hippocampus of Aldh2−/− mice and in formaldehyde-injected SD rats, which ultimately prevented their memory decline (Ai et al. 2019). To test CoQ10 functioning in scavenging formaldehyde, male C57BL/6 mice were orally pre-administrated with nano-packed CoQ10 for three days and then treated with acute hypobaric hypoxia. Significantly, CoQ10 lowered the level of formaldehyde in the brain and rescued neurological function in C57BL/6 mice through its ability to bind to formaldehyde, preventing the expression of SSAO and increasing the expression and activity of ALDH2 (Wang et al. 2022a). Silibinin, a flavonoid compound prepared from Silybum marianum, also improved cognitive deficits in C57BL/6 mice that had been injected with formaldehyde in their lateral ventricle. One of the mechanisms by which silibinin improves cognitive disorders could be attributed to its ability to increase the expression of both ALDH2 and ADH3 (Wei et al. 2022). These data demonstrated that ALDH2 acts as an effective target to prevent formaldehyde accumulation in vivo.

3.2 GSH-Dependent Pathway

GSH, a thiol-containing tripeptide, is able to act as an important antioxidant to prevent carbonyl derivatives generated through lipid peroxidation (Palamanda and Kehrer 1992). During the detoxification process, GSH must cooperate with a series of enzymes, including GSHRx, GSHPx, and GSH S-transferase (GSHST). Koivusalo et al. showed that formaldehyde is catalyzed by FDH, which is also known as class III alcohol dehydrogenase (alternative abbreviation ADH3 or ADH5), in a GSH-dependent pathway (Koivusalo et al. 1989; Bae et al. 2017; Zhang et al. 2019). First, formaldehyde reacts with GSH to form S-hydroxymethyl GSH in a nonenzymatic reaction. Second, S-hydroxymethyl GSH is transformed into S-formyl GSH catalyzed by ADH3 in the presence of NAD⁺. Finally, S-formyl GSH hydrolase, also called esterase D (ESD), irreversibly catalyzes S-formyl GSH to form GSH and formate (MacAllister et al. 2011; Chen et al. 2020). Similarly, formate is metabolized to CO₂ in further reactions. Hedberg et al. indicated that ADH3 is a major enzyme for the prevention of formaldehyde toxicity in human oral mucosa (Hedberg et al. 2000). According to Qiang et al’s work, enzymatic activity, mRNA, and protein levels of ADH3 were also lower in the brains of SAMP8 mice than in those of SAMR1 mice. This may lead to relatively higher levels of formaldehyde in the brains of SAMP8 mice than in those of SAMR1 mice (Qiang et al. 2014).

Elevation of the formaldehyde content was also observed in the brains of APP/PS1 mice when compared with wild-type C57BL/6 mice. The high formaldehyde level was due to low FDH activity in the brains of the APP/PS1 mice. As described by Yue et al. Aβ42 suppressed FDH activity by breaking the disulfide bonds formed between cysteine-103 and cysteine-111, which in turn promoted formaldehyde accumulation (Yue et al. 2019). Furthermore, Aβ42 can bind to FDH in the mitochondria of the brain, leading to FDH oligomerization and inactivation, and ultimately promoting the accumulation of formaldehyde (Fei et al. 2021). After HU- stress (see Sect. 2.5.1), the lower protein level and activity of FDH in the cerebellum could also be among the reasons for the increased formaldehyde in the cerebellum and gastrocnemius of the C57BL/6 mice. Formaldehyde also accumulates in the muscle and cerebellum in FDH−/− knockout mice (Yao et al. 2021). Taken together, the GSH-dependent ADH3 (ADH5 or FDH) may be an important enzyme to eliminate the damage caused by endogenous formaldehyde.

Although S-nitrosoglutathione reductase (GSNOR) plays an important role in the protein S-nitrosation process, it was originally identified as ADH5, which belongs to the alcohol dehydrogenase (ADH) family (Barnett and Buxton 2017; Casin et al. 2018). GSNOR favors two major substrates, S-nitrosoglutathione and S-hydroxymethyl GSH, in addition to some alcohols (Barnett and Buxton 2017; Casin et al. 2018). Thus, GSNOR is believed to metabolize formaldehyde. After ischemia, formaldehyde accumulated in the hearts of GSNOR knockout mice and N6022-treated (an inhibitor of GSNOR) female mice. Alda-1, an ALDH2 activator, was found to reduce the infarct size in female GSNOR knockout mice. These data suggest that formaldehyde accumulation caused by GSNOR inactivity may promote myocardial ischemia reperfusion injury in female hearts (Casin et al. 2018).

As ADH3 (ADH5 or FDH) is another effective enzyme that metabolizes formaldehyde in vivo, some strategies have tried to suppress formaldehyde accumulation by affecting ADH3 (ADH5 or FDH). For example, after exposure to LED-RL, SAMP8 mice displayed improved spatial learning and memory abilities when compared with mice with sunlight lamp treatment (Zhang et al. 2019). Illumination with LED-RL could upregulate the expression of FDH and recover its activity in the brains of SAMP8 mice, which is one of the factors accounting for the reduction of brain formaldehyde levels. Although H₂O₂ can inactivate FDH, LED-RL treatment restored its activity by preventing catalytic Zn²⁺ release and cysteine-45 oxidation (Zhang et al. 2019). Similarly, when the APP/PS1 mice were illuminated with LED-RL (five days per week) for two months, the activity of FDH was enhanced, followed by a significant decrease of formaldehyde in the brain and liver of the mice. LED-RL exposure seems to restore FDH activity by re-formation of disulfide bonds between cysteine-103 and cysteine-111, which are affected by Aβ42 (Yue et al. 2019). After that, a red-light treatment (RLT) device (630 nm) was safely used as an adjuvant treatment for mild to moderate AD patients (Huang et al. 2020). In addition, RL coupled with intragastric CoQ10 was proven to prevent formaldehyde accumulation significantly in the muscle and cerebellum of the HU-stress mice, probably through an increase in FDH activity (Yao et al. 2021).

3.3 Intestinal Microbiota

The gut/gastrointestinal tracts, which contain the microbes, generate, process, and scavenge formaldehyde (see Chaps. 7 and 18). The assimilation and dissimilation pathways of formaldehyde in gut bacteria could contribute to the metabolism of endogenous formaldehyde in physiology and pathology for humans (Li et al. 2016a, b; Marx et al. 2003; Mei et al. 2015; Vorholt et al. 2000).

3.4 Reaction with THF

As previously described by Kallen and Jencks, the formaldehyde generated from one-carbon circle could also react with THF to form 5,10-methylene-THF (Kallen and Jencks 1966). As we all know, THF is an important cofactor during the synthesis of amino acids and nucleic acids. Thus, the interaction between formaldehyde and THF might also be another pathway that decreases the level of free formaldehyde in vivo (Kallen and Jencks 1966). The authors proposed that thiols could inhibit the condensation of formaldehyde with THF since thiols react with formaldehyde with the formation of hemithioacetal at neutral and alkaline pH. Furthermore, THF could compete with thiols to bind to unhydrated formaldehyde (Kallen and Jencks 1966). In 2017, Burgos-Barragan et al. used [¹³C] formaldehyde to prove that the 1C units originating from formaldehyde were responsible for the synthesis of nucleotide (adenosine triphosphate, ATP) in an ADH5-dependent manner (Burgos-Barragan et al. 2017).

3.5 Reaction with Biomacromolecules Such as Protein, DNA, and RNA

In live organisms, formaldehyde is usually produced within cells, and this toxic molecule can be metabolized through mitochondrial ALDH2 pathway, GSH-dependent pathway, intestinal microbiota, or THF. If the dynamic equilibrium between formaldehyde generation and clearance is destroyed, the excess formaldehyde will accumulate, react with biomacromolecules, including protein, DNA, and RNA, and finally have harmful impacts on their biological functions.

3.5.1 The Reaction Between Formaldehyde and Proteins

In daily experiments, formaldehyde is usually used as a fixing factor or cross-linking reagent to study the distribution of biomacromolecules in cells and tissues. In the 1930–1950s, formaldehyde was reported to react with proteins by forming methylene cross-links (Clark and Rowan 1938; Fraenkel-Conrat and Olcott 1948). With the many efforts from scientists all over the world, the mechanisms of the cross-links generated between formaldehyde and proteins have been illustrated in detail. First, the α/ε-amino group and thiol of amino acid residues could react with formaldehyde to form methylol adducts (Metz et al. 2004). Next, the methylol adducts of the amino groups are dehydrated to generate an imine, which is also named the Schiff base (Metz et al. 2004). Finally, labile imine could further form cross-links with a battery of residues, including arginine, asparagine, cysteine, glutamine, histidine, tryptophan, and tyrosine (Metz et al. 2004). Therefore, formaldehyde could induce intramolecular and intermolecular cross-linkages between protein residues. In 2004, Metz et al. analyzed the products from peptides modified by formaldehyde through tandem reversed-phase liquid chromatography and electrospray ionization mass spectrometry (LC/MS) (Metz et al. 2004). Their study tried to observe the different modifications of every individual amino acid residue induced through formaldehyde and found that peptides’ (or proteins’) different sequences determined the formaldehyde modification types, including methylol groups, Schiff bases, and methylene bridges (Metz et al. 2004). In 1996, Yu et al. found that formaldehyde from the deamination of methylamine mediated by SSAO might lead to the formation of irreversible adducts of proteins in vivo (Yu and Zuo 1996). They speculated that the generated formaldehyde, H₂O₂, and formaldehyde-modified proteins might be risk factors for the formation of endothelial injury and initiation of atherosclerosis (Yu and Zuo 1996). In 2004, Gubisne-Haberle et al. further studied the products after formaldehyde modification (Gubisne-Haberle et al. 2004). They observed that formaldehyde generated from methylamine deamination could effectively induce bipeptide (H-Lys-Leu-OH) cross-linkage, which is unstable in 6 N HCl. This finding suggested that Schiff bases between two free ε-amino groups of lysine residues were formed in the presence of formaldehyde (Gubisne-Haberle et al. 2004). After reduction by sodium cyanoborohydride, the Schiff bases are converted to N-methyl-lysine and formyl-lysine (Gubisne-Haberle et al. 2004). In addition to bipeptides, the authors also used mouse intestines, which are rich in SSAO activity, to produce formaldehyde to further modify bull serum albumin (BSA) (Gubisne-Haberle et al. 2004). Similar to the data from bipeptide, N-methyl-lysine originating from the hydrolyzed proteins was also found by HPLC. Importantly, after modification by formaldehyde, proteins might lose their original functions and become pathogenic agents that are related to various diseases, including vascular disorders, chronic heart failure, diabetic complications, and AD (Gubisne-Haberle et al. 2004). Furthermore, endogenous formaldehyde was also proven to participate in the formation of N⁶-formyllysine, which could disturb the functions of other posttranslational modifications (Edrissi et al. 2013). In 2006, Chen et al. demonstrated that formaldehyde can significantly trigger β-sheet, oligomer, protofibril, and even aggregate formation from seed-free Aβ1–40 in vitro (Chen et al. 2006). Recently, formaldehyde was reported to interact with lysine-28 of Aβ42 to form oligomers and fibrils in both in vitro and in vivo studies, which finally led to the aggregation of Aβ (Fei et al. 2021). In 2018, formaldehyde was found to react with insulin and form formaldehyde-insulin aggregates in SD rats that had been injected with formaldehyde for eight weeks. These aggregates made insulin lose the ability to decrease the content of blood glucose (Tan et al. 2018). As excess formaldehyde (450 μM) would lead to the cross-link between cysteine-79 of NR1 and lysine-79 of NR2B of the NMDA-type glutamate receptor, the NMDA current was inhibited, which further caused spatial memory impairment in SD rats (Ai et al. 2019).

3.5.2 The Reaction Between Formaldehyde and Nucleic Acids

In addition to proteins, formaldehyde can also trigger the inactivation of nucleic acids, including DNA and RNA. Similar to the protein adducts modified by formaldehyde, labile aminomethylol (−NHCH₂OH), Schiff base (−N=CH₂), and stable methylene (R-CH₂-R’) derivatives are generated when formaldehyde reacts with nucleic acids (Feldman 1967; Penniston and Doty 1963). Among the derivatives, the -NHCH₂OH derivatives could release formaldehyde after dilution. Thus, the derivatives are usually undetectable due to their instability. The stable R-CH₂-R’ derivatives need two steps to form: the first stage is the formation of methylol derivatives (RH + CH₂O ⇌ R-CH₂OH), and the second stage is the formation of methylene derivatives (R-CH₂OH + RH ⇌ R-CH₂-R + H₂O) (Feldman 1967). At this stage, the generated methylene derivatives are more stable. Chaw et al. purified the cross-links generated between formaldehyde and exocyclic amino groups of the bases in DNA or RNA through reverse-phase high-pressure liquid chromatography (Chaw et al. 1980). After analysis by a series of methods, including ultraviolet or nuclear magnetic resonance (NMR) spectroscopy, both cytosines and purines were found to be involved in the methylene-bridged products (Chaw et al. 1980). In 2020, Dingler et al. detected the content of N²-methyl-deoxyguanosine, which is derived from the unstable formaldehyde adduct N²-hydroxymethyl-deoxyguanosine, and showed that its level was significantly increased in the DNA from the livers, kidneys, and brains of Aldh2−/−Adh5−/− mice, suggesting that formaldehyde is able to induce DNA damage. They proposed that formaldehyde is liable to react with the exocyclic amine of adenine (Moeller et al. 2011; Dingler et al. 2020). Formaldehyde also attacks the “imino” groups of thymine and uracil derivatives (McGhee and von Hippel 1975). During this reaction, the N-3 proton is converted to a hydroxymethyl or methylol group (McGhee and von Hippel 1975). Interestingly, even though the secondary structure from both RNA and DNA is different, the cross-links generated between formaldehyde and RNA or DNA were similar (Chaw et al. 1980). In addition to the multiple studies on the structure of adducts formed from formaldehyde and DNA or RNA, the side effects of these adducts have also been a focus for a very long time. To date, we can confirm that DNA or RNA after aberrant modification by formaldehyde should be a potential risk for gene mutation and genome instability.

3.5.3 The Cross-Links of Proteins and Nucleic Acids Induced by Formaldehyde

Although reaction with formaldehyde would lead to the inactivation of proteins, DNA, or RNA, formaldehyde, which acts as an ideal fixer, is usually used to stabilize and characterize the complex generated between proteins and DNA in vitro. Therefore, it is likely that excess endogenous formaldehyde might have the potential to induce covalent DNA–protein cross-links (DPCs or DPX), which would cause proteins or DNA to lose their original functions and finally cause cancer. As early as 1983, Casanova-Schmitz and Heck observed that formaldehyde could induce cross-links between proteins and nucleic acids in vitro (Casanova-Schmitz and Heck 1983). Furthermore, they also treated rats with formaldehyde, and the content of DPX was increased in the respiratory mucosa of the rats (Casanova-Schmitz and Heck 1983). Therefore, the newly formed DPX with genotoxicity might be one of the pathogenic factors triggering cancer. In 2010, Lu et al. characterized the structure of DPCs formed from lysine, cysteine, histidine, and tryptophan with deoxyguanosine, deoxyadenosine, and deoxycytosine (Lu et al. 2010). Among the cross-links, lysine is liable to react with deoxyguanosine (Lu et al. 2010). In general, there are two routes accounting for the generation of DPCs. One route is that the electrophilic carbon of formaldehyde attacks the nucleophilic site of proteins, and subsequently, the methylol adduct of proteins reacts with the nucleophilic site of DNA to form DPCs (Kennedy-Darling and Smith 2014). The other route is that formaldehyde initially attacks the nucleophilic site of DNA, and its methylol adduct further forms cross-links with the residue in protein (Lu et al. 2010). DPCs are pervasive DNA lesions, which interfere with essential chromatin processes such as transcription or replication. Weickert and Stingele emphasized that loss of DPCs’ repair capacity has dramatic and harmful consequences, ranging from genome instability to cancer predisposition and premature aging (Weickert and Stingele 2022).

4 Conclusion

Formaldehyde comes from many different metabolic pathways but goes away through a relatively narrow degradation lane in human cells. Among the “coming” pathways, formaldehyde resulting from methanol is one of the main metabolic pathways because humans take methanol from food. In addition, cellular oxidative stress is also one of the most common pathways to produce endogenous formaldehyde. H₂O₂ triggers the production of formaldehyde through cellular oxidative stress. In addition to those pathways, DNA, RNA, and protein demethylation also produce plenty of formaldehyde. It should never be forgotten that the intestinal flora regulates formaldehyde generation, process, and clearance.

As shown in Fig. 2.6, almost all organelles are involved in biochemical reactions with formaldehyde, such as mitochondria (Xin et al. 2019), peroxisomes (Zhang et al. 2014), microsomes (Winters et al. 1988), lysosomes (Chen et al. 2017; Cao and Ma 2022), nuclei (Shi et al. 2004; Tong et al. 2013; Li et al. 2021), cellular granules (Loria et al. 2008), and vesicles (Gellhaar et al. 2017), in addition to the cytosol. This suggests that formaldehyde is highly active in live cellular processes. The metabolism of formaldehyde may be disturbed by the dysfunction of those organelles. For instance, formaldehyde can cause mitochondrial DNA damage (Nadalutti et al. 2021). Formaldehyde is generated through the one-carbon formaldehyde cycle in mitochondria, and abnormal elevations in formaldehyde levels can damage mitochondria by decreasing the mitochondrial membrane potential and inhibiting mitochondrial respiration (Xin et al. 2019). Granules (Loria et al. 2008) and vesicles (Gellhaar et al. 2017), which contain MPO, are involved in formaldehyde metabolism. Markedly increased MPO-immunoreactive cells in brain were associated with neurodegenerative diseases such as AD and PD, supporting research of inhibitors of MPO in novel treatment strategies.

Fig. 2.6

The organelles involving formaldehyde in a cell

In the “going” pathways, the conversion of formaldehyde to formic acid and then to CO₂ and water is the most important pathway in degradation. The metabolic homeostasis of endogenous formaldehyde is maintained by the activities of generation and degradation pathways, which are complicated and diversified. Dysfunction of either the generation or degradation pathways, which will result in a lack or excess of formaldehyde, leads to an imbalance of the metabolic formaldehyde. Dysmetabolism is one of the risk factors related to the onset of age-cognitive impairment. The ability of humans to scavenge endogenous formaldehyde is much weaker than that of rodents (Klaassen 2001). Humans have to face many endogenous metabolic products, including formaldehyde, daily, which needs to be processed and scavenged. Cellular organelles such as lysosomes, mitochondria, and peroxisomes are involved in formaldehyde processing. Following the development of fluorescent biomarkers to probe endogenous formaldehyde in living cells, lysosomes were found to act as a major organelle to accommodate and transport formaldehyde in a cell. Now, the fluorescent probe is able to specifically detect and image formaldehyde in living cells (Cai et al. 2021; Cao and Ma 2022). Dysfunction of lysosomes could lead to an imbalance in formaldehyde metabolism, for instance, formaldehyde was detected increased in dysfunctional lysosomes of PD (Quan et al. 2023).

As we know, the ability to process and scavenge becomes weaker with aging (Tong et al. 2013; Tang et al. 2016), resulting in chronic accumulation of metabolic products in vivo, including formaldehyde at least. However, Louveau et al. revealed that the structure and function features of lymphatic vessels in CNS (Louveau et al., 2015). After that, CSF is reported to discharge through the arachnoid villi or along the spinal cord and cranial nerves or through meningeal lymphatic cells. It flows into the bone marrow of the skull through the cranial passages (Pulous et al. 2022; Mazzitelli et al. 2022). As described by Yoon et al. the nasopharyngeal lymphatic plexus acts as a hub for CSF drainage (Yoon et al. 2024). As we know, methanol and formaldehyde can also transport from blood circulation to intercellular fluid through the blood cerebral barrier and vice versa. Thus, it indicates that the CNS lymphatic drainage system should be a potential target in the treatment of age-related cognitive impairment (Ren and Ye 2024). It can be predicted that elimination of adverse metabolic products (Aβ, pTau, and probably formaldehyde, formic acid, and other adducts) from cerebral tissues through lymphatic drainage system by surgery or some other treatments, for instance improving microcirculation by lumbrokinase, will have a good therapeutic prospect. As shown in Fig. 2.7, cerebral adverse metabolic products such as methanol (MeOH), formaldehyde (HCOH), and formic acid (HCO₂H) are eliminated through CSF, blood circulation, and renal excretion via urine. The adverse adducts have been tested out in cerebral tissues (Tong et al. 2011; Su et al. 2011), CSF (Li et al. 2020), blood (He et al. 2010), and urine (Wang et al. 2022b; Chen et al. 2022). Xie’s team treated AD patients through processing a surgical operation of “cervical lympho-venous anastomosis” (Xie et al. 2024) to improve the central lymphatic drainage (Ren and Ye 2024), and discharge adverse products including Aβ, pTau, and probably formaldehyde, formic acid, and other adducts.

Fig. 2.7

A scheme for the elimination of cerebral adverse metabolic products such as methanol (MeOH), formaldehyde (HCOH), and formic acid (HCO₂H) through CSF, blood circulation, and kidney by urine

Acknowledgments

All grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_3

3. Formaldehyde and Catecholamine Neurotransmitters in Cognitive Impairment

Juanjuan Ji¹ and Rongqiao He1  

(1)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Catecholamines such as norepinephrine (NE) and dopamine mediate a variety of the central nervous system functions, including cognition, memory processing, emotion, motor control, and endocrine modulation. Formaldehyde is closely related to functions of catecholamine neurotransmitters, because (1) formaldehyde is able to react with the alpha-amine group of catecholamines directly and inactivate the transmitter’s function; (2) as a methyl group donor, formaldehyde participates in catecholamine metabolism and 3-O-methylation occurs on catecholamines to be inverted to inactive 3-O-methyl-metabolites in the presence of catechol-O-methyl transferase (COMT) through formaldehyde cycle; (3) also as a methyl group donor, formaldehyde cycle is involved in the conversion of norepinephrine to epinephrine catalyzed by phentolamine N-methyltransferase. Furthermore, aging is associated with formaldehyde accumulation and norepinephrine deficiency in the hippocampus. It is reasonable that formaldehyde accumulation induces hippocampal norepinephrine deficiency, which in turn leads to memory decline during the aging process. Scavenging formaldehyde from or supplying norepinephrine to the hippocampus can rescue memory deficits in aged rats. This chapter focuses on the relationship between formaldehyde and the catecholamine neurotransmitter in the synthesis, function, and neurodegenerative disease, especially age-related cognitive impairment.

Keywords

Endogenous formaldehydeAlzheimer’s diseaseN-methyl-D-aspartate receptorLong-term

Abbreviations

A

ACC

Anterior cingulate cortex

AChE

Acetylcholinesterase

AD

Alzheimer’s disease

ALFA

Aluminum-formaldehyde

C

COMT

Catechol-O-methyl transferase

CSF

Cerebrospinal fluid

F

FDH

Formaldehyde dehydrogenase

FIF

Formaldehyde-induced fluorescence

G

GDH

Glutamic dehydrogenase

L

LC

Loci coerulei

LDH

Lactate dehydrogenase

LTP

Long-term potentiation

M

MAO

Monoamine oxidase

MGF

Mangiferin

MHPG

3-methoxy-4-hydroxyphenylglycol

N

NA

Noradrenaline

NE

Norepinephrine

P

PD

Parkinson’s disease

PNMT

Phentolamine N-methyltransferase

S

SSAO

Semicarbazide-sensitive amine oxidase

SAMP8

Senescence accelerated prone 8

O

6-OHDA

6-hydroxydopamine

1 Introduction

When taking a rest in the quiet night, we enjoy the endless Milky Way; when the sea breeze touches the face of the waves flying, our thoughts run with the deep sea; when stepping on the black earth, we look out on the vast deep forest or further. As summer turns to fall and nature becomes more colorful and charming, we are truly grateful to nature for endowing a sophisticated nervous system to us that allows us to sense and respond appropriately to the changing world. All these are inseparable from the nervous system perception, information transmission, and processing. In the complex networks of the nervous system, there is a special structure for the exchange of information between neurons, called synapse. Neurotransmitters participate in synaptic activity, that is, presynaptic release of neurotransmitters, acting on the receptors in the postsynaptic membrane, resulting in a series of biological effects. It is indispensable for the neurotransmitters as messenger molecules that act for information transmission and processing in our brain.

In the nervous system, the structure and function of neurons and glial cells follow universal rules of physicochemistry to regulate animal behavior, including perception, movement, exploration, and decision-making. Why do we wake up from deep sleep? In the state of arousal, what neurophysiological mechanisms enable us to enjoy delicious food, pursue personalized fashion, travel to other places, and maintain a healthy lifestyle; keep us alert to dangers, triggering fear and impulses (fight-or-flight) when encountering a wild animal, so that we can stay alert to danger; and guide us in research and work? Our answer is that all those result from a class of monoamine neurotransmitters in the nervous system, such as catecholamines and serotonin, which are involved in our emotions, movement, learning, memory, and so on (Kobayashi 2001).

Formaldehyde exists in the universe, along with the birth and development of the earth, and with the reproduction and evolution of life (Bear et al. 2016; Park et al. 2018). On the one hand, formaldehyde exists in the environment (exogenous formaldehyde) such as the atmosphere (from plant metabolism and forest fires), automobile exhaust, cigarette smoke, and some hydrocarbon pollutants such as methane which could be oxidized to the intermediate products of formic acid in the working and living environment (Jonsson 1969). People’s general concern about exogenous formaldehyde mainly originates from environmental pollution, including the excessive content of formaldehyde in building decoration materials, food additives, pesticides, and industrial smog (Einarsson et al. 1975; Guo et al. 2005). On the other hand, formaldehyde is also produced in organisms (endogenous formaldehyde), resulting from the demethylation of DNA, RNA, histone, glycan, etc. Endogenous formaldehyde is present in all cells and their microenvironment (Nygren 1976). The concentration of formaldehyde in human blood is about 0.08 mmol/L, and in the brain tissue, 0.2–0.4 mmol/L under physiological conditions (Epperlein 1978; Loren et al. 1982). The “formaldehyde cycle“(see Chap. 11) regulates epigenetic inheritance, and cell function in humans and animals (Chen et al. 2022).

Physiologically, formaldehyde participates not only in the degradation of monoamine neurotransmitters, but also in the synthesis of epinephrine and melatonin from serotonin (see Chap. 11). Pathologically, dysregulation of formaldehyde metabolism directly or indirectly affects the metabolism and function of those neurotransmitters, thereby causing damage to the nervous system and related behaviors, including cognitive impairment (Alzheimer’s disease, AD), movement (Parkinson’s disease, PD), and mood (anxiety and depression). Therefore, in this chapter, we focus on the relationship between formaldehyde and monoamine neurotransmitters, especially norepinephrine, in order to deepen the understanding of the neurobiological function of this smallest and simplest organic molecule.

2 Catecholamine and Formaldehyde

In 1945, norepinephrine’s role in the body was discovered by Dr. Ulf van Euler at the Karolinska Institute (Solna, Sweden); he shared the 1970 Nobel Prize in Physiology or Medicine for his work on neurotransmitters. Norepinephrine (NE) or noradrenaline (NA) is a natural compound belonging to the catecholamine family that acts as a neurotransmitter and hormone. In the presence of dopamine β-hydroxylase, norepinephrine is synthesized directly from dopamine in four steps from tyrosine and then stored in presynaptic vesicles. As a direct precursor to epinephrine, norepinephrine is strongly associated with bringing our nervous systems into “high alert” in terms of “fight or flight.” Norepinephrine functions as a multiply excitatory neurotransmitter through specific receptors in distinct brain regions-stimulates activity in the brain, boosting the function of different cells to keep your brain and body running efficiently. It elevates blood pressure by triggering vasoconstriction and increasing heart rate. In fact, norepinephrine is one of the neurotransmitters essential for a variety of functions that help maintain your health. Moreover, the synthesis and breakdown of norepinephrine are intimately connected to the operations of the entire catecholamine system.

Formaldehyde and catecholamine had a certain story from the beginning. In the mid-1960s, using formaldehyde, Fuxe and his coworkers at the Karolinska Institute in Sweden selectively visualized the catecholaminergic neurons in histological sections prepared from the brain (Bear et al. 2016). As depicted by them, norepinephrine-containing neurons in the locus coeruleus were visualized in green fluorescence with the treatment of formaldehyde gas. This technique revealed that neuronal axons project from the locus coeruleus in several tracts, and fan out to innervate just about the entire brain: neocortex, limbic system, cerebellum, and spinal cord. The cryostat sections were incubated in glyoxylic acid, dried, and reacted with formaldehyde vapor, resulting in the staining and exhibiting the neurons. Earlier studies have given a reasonably theoretical explanation (Jonsson 1969; Einarsson et al. 1975), and this reaction has been verified by synchronous fluorimetry to detect NE concentration (Guo et al. 2005). In addition, formaldehyde-derived tetrahydroisoquinolines and tetrahydro-beta-carbolines from the reaction with catecholamines were detected in human urine samples (Musshoff et al. 1996).

Using this technique, cortical-noradrenaline- and dopamine-containing nerve terminals could be visualized with high sensitivity in a reproducible way (Nygren 1976). Neural crest-derived neuroblasts and melanoblasts exhibited catecholamine-positive reactions upon formaldehyde-induced fluorescence (FIF). In contrast, axons from the brain derivative were catecholamine-negative but acetylcholinesterase (AChE)-positive (Epperlein 1978). The experiments indicate that epinephrine can react with formaldehyde (HCHO) in an acid medium to form a condensation product that can be oxidized by potassium hexacyanoferrate (III) (K₃[Fe(CN)₆]) in borax buffer (pH = 9.5). The reaction product can emit strong fluorescence (Hartwig et al. 1979, Gao et al. 2005). The aluminum-formaldehyde (ALFA) histofluorescence method was established to improve visualization of catecholamines and indoleamines (Loren et al. 1980, 1982). In a circumscribed area of the preoptic periventricular nucleus of a male rat, formaldehyde-induced monoamine fluorophores modified by treatment with HCl vapors were investigated microfluorometrically (measurement of excitation peak ratio 370∶320 nm) in all fluorescent terminals and preterminals.

3 Formaldehyde Involving Cognitive Impairment

Since formaldehyde is reacted with every monoamine neurotransmitter differently, the interaction between formaldehyde and catecholamine (dopamine, norepinephrine and epinephrine) and serotonin should be considered in cognitive impairment reasonably. This viewpoint is based on these observations. First, it was described that endogenous formaldehyde may be accumulated in AD patients. Urine formaldehyde levels are involved in AD progression and are a potential useful biomarker for clinical auxiliary diagnosis (Chen et al. 2022). Second, endogenous formaldehyde accumulation was observed not only in the brains of aged mice, APP/PSI transgenic mice (Balducci and Forloni 2011), and the senescence accelerated prone 8 (SAMP8) mice (Qiang et al. 2014), but also in the hippocampi of patients with AD (Tong et al. 2013b). Third, formaldehyde is able to induce AD-like pathologies and cognitive impairments in Nonhuman primates (Zhai et al. 2018). Fourth, inhibiting formaldehyde metabolic enzymes or injecting excess formaldehyde directly induces deficits in long-term potentiation (LTP) and memory in healthy adult rats (Tong et al. 2013a, b). Fifth, AD is characterized by beta-amyloid deposit, Tau phosphorylation, glial cell hyperactivation, and neuronal loss (Park et al. 2018). Formaldehyde in excess induces Tau hyperphosphorylation (Yang et al. 2014a) and Abeta deposition (Yang et al. 2014b). Sixth, scavenging formaldehyde by injecting Mangiferin (MGF, a natural C-glucosyl-xanthone with promising neuroprotective effects) (Chen et al. 2023) and resveratrol (also a natural product) (Tyihak et al. 1998; Tong et al. 2011; Miao et al. 2013; He et al. 2017) were found to reduce FA levels in neuronal cells, mouse brain and hippocampus, and ameliorate memory impairment in naturally aging mice (Chen et al. 2023) and APP-transgenic mice (Karuppagounder et al. 2009), and aged rats. Finally, both formaldehyde and norepinephrine are involved in learning and memory as mentioned in the text. It has been shown that formaldehyde accumulation is related to norepinephrine deficiency in rat brain (Mei et al. 2015).

Norepinephrine is also important for forming memories. Crow (1968) raised a hypothesis that the adrenergic system plays a role in learning and memory (Crow 1968). After that, biogenic amines were considered playing roles in arousal, emotion, and learning in the central nervous system (Kety 1970). Hippocampal norepinephrine acts as a neurotransmitter that is required for learning and memory (Gelinas et al. 2007). This is based on the fact that injection of NE or antagonist of NE receptor can enhance or block hippocampal long-term potentiation (LTP) and memory formation (Gray and Johnston 1987; Izumi and Zorumski 1999). Accumulating evidences indicate that memory decline associated with NE deficiency has been found in aged animals (such as mice and rats) and in transgenic AD mice, TgCRND8 (Luine and Hearns 1990; Francis et al. 2012). Clinical investigations also find that there are irregularities in NE content in the blood and cerebrospinal fluid (CSF) of older and patients with AD (Peskind et al. 1995; Szot et al. 2000), and a marked NE deficiency or norepinephrinergic neuron loss in the autopsied hippocampi and loci coerulei (LC) of AD patients (Chan-Palay and Asan 1989). Furthermore, depletion of hippocampal NE by injection of 6-hydroxydopamine (6-OHDA, an NE depletor) or N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, a selective norepinephrinergic neurotoxin) has been found to induce deficits in LTP and memory in healthy adult rats (Stanton and Sarvey 1985; Lapiz et al. 2001). Studies on norepinephrine and its involvement in learning and memory have received increasing attention in recent years (de Leo et al. 2023; Goulty et al. 2023; Isingrini et al. 2023). All these data suggest that age-related norepinephrine deficiency contributes to cognitive disorder during aging and AD processes. However, which endogenous factor induces NE deficiency still needs to be elucidated.

4 Reaction of Formaldehyde with Catecholamine

The reaction of formaldehyde with catecholamine probably occurs in non-enzymic and enzymic manners. (1) In the non-enzymic process, formaldehyde reacts directly with the alpha-amino group of catecholamines through Schiff’s reaction in vivo and in vitro. Norepinephrine and epinephrine can be condensed with formaldehyde or acetaldehyde in dilute aqueous solution at room temperature (pH = 7.0) to form 1,2,3,4-tetrahydroiso-quinoline alkaloids (Cohen and Collins 1970). (2) Either monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT) is involved in the metabolism of catecholamine neurotransmitters (Burgos-Barragan et al. 2017), in which formaldehyde acts as a methyl donor in one carbon cycle or called by formaldehyde cycle (Tyihak et al. 1998). (3) Formaldehyde also plays a role in alpha-N-methylation from norepinephrine to epinephrine catalyzed by phentolamine N-methyltransferase (PNMT) through the formaldehyde cycle (Mahmoodi et al. 2020). Levels of norepinephrine or other catecholamines could be lowered in the presence of formaldehyde due to these reactions. This may be one of the reasons why formaldehyde can quickly deactivate norepinephrine in the synaptic cleft, and explains the low norepinephrine levels associated with a high formaldehyde concentration that was detected in the hippocampus (Mei et al. 2015).

It has been demonstrated that a decline in norepinephrine in the hippocampus is associated with cognitive deficits, particularly in aged rats (Bickford 1993) and AD patients (Chalermpalanupap et al. 2013). As described by Cohen and Collins (1970), formaldehyde accumulation contributes to the depletion of norepinephrine or epinephrine in vitro and in vivo. Further investigation by intrahippocampal injection of aldehyde confirmed that the elevation of formaldehyde decreased the hippocampal norepinephrine levels (Mei et al. 2015). Conversely, they performed an intrahippocampal injection of norepinephrine and observed a marked decrease in the concentration of hippocampal formaldehyde, which suggested an inverse relationship between formaldehyde and norepinephrine levels in the hippocampi of normal rats at different ages.

4.1 Reaction Without Enzymic Catalysis

Formaldehyde is able to efficiently traverse the blood–brain barrier including cell membranes (Tulpule and Dringen 2012). On the basis of the chemical structure of formaldehyde and catecholamine, a schematic view probably depicts the common formaldehyde-induced modifications in dopamine, norepinephrine, or epinephrine. The initial rapid reaction between formaldehyde and the amino group of catecholamines forms reactive methylol adducts (Dm = +30 Da), followed by a slow condensation reaction of the adducts leading to methylene bridges with the catecholamine through a Schiff base (Dm = +12 Da) formation (Nirmalan et al. 2008). It is possible that the Schiff base can further bind another catecholamine to its amino group. A cross-linking reaction may occur between the molecules including protein, DNA, or RNA, and it directly inactivates the catecholamine (Metz et al. 2004; Yun et al. 2018). Norsalsolinol is one of the adducts from the reaction between formaldehyde and dopamine after the Schiff’ base formation (Yu et al. 2003). Tani et al. (1981) observed that formaldehyde inhibits vascular muscle contraction in rabbits, which is due to formaldehyde directly inactivating norepinephrine (Tani 1981). An experiment in vitro by Mei et al. supported this view. They incubated 0.2 mM formaldehyde with 0.2 mM norepinephrine in a phosphate buffer (at 37 °C) and observed a marked decrease in both compounds after a 3-hour reaction (Mei et al. 2015). Miraculously, they demonstrated the proportion of chemical reaction between NE and FA with a ratio of 1/2. These data probably suggest the occurrence of a direct reaction between formaldehyde and catecholamine in vivo.

4.2 Involving Catecholamine Breakdown

Catechol-O-methyl transferase (COMT) is one of the main enzymes involved in the breakdown of monoamine neurotransmitters (dopamine, norepinephrine, epinephrine), which play a key role in different aspects of the human brain, such as schizophrenia (Sagud et al. 2010, 2023), bipolar disorder (Hosang et al. 2017), suicide (Pivac et al. 2011), and memory (Giakoumaki et al. 2008; Fan et al. 2020). Either monoamine oxidase (MAO) or COMT is involved in the first steps in the breakdown of these neurotransmitters, which depends on different reaction pathways. As shown in Fig. 3.1, catecholamine is methylated and inverted to inactive 3-O-methyl-metabolites in the presence of COMT (Tsunoda et al. 1999; He et al. 2012). In the reaction, the formaldehyde cycle provides a methyl group to catecholamine (Tyihak et al. 1998; Kalasz 2003; Bae et al. 2017; Burgos-Barragan et al. 2017). Dopamine, norepinephrine, or epinephrine will be inactivated when methylation occurs on the 3-OH site of catecholamine.

Fig. 3.1

Diagram for formaldehyde involving catecholamine breaking down through formaldehyde cycle. Formaldehyde as a donor for the methylation through formaldehyde cycle, which was adapted from Fig. 4.​1 in Chap. 4. SAH, S-adenosyl-L-homocysteine; SAM, S-adenosyl-L-methionine

The formaldehyde cycle is in dynamic equilibrium under the physiological condition to maintain homeostasis of methylation and demethylation (Morellato et al. 2021). On the basis of those observations, it can be speculated that if the concentration of formaldehyde in the brain is abnormally high, more formaldehyde will enter the formaldehyde cycle, providing a methyl group. This could lead to more catecholamine 3-O-methylation, resulting in a loss of neurotransmitter activity. Studying the structure and function of COMT may help us understand the underlying mechanisms of several psychiatric disorders associated with impairment in decision-making (He et al. 2012). On the other hand, methylation and demethylation of DNA, RNA, and histones will also be disturbed if the formaldehyde cycle dysfunctions. Recently, using the network pharmacology-based approach, Li et al. (2022) investigated the mechanisms of Zingiber officinale roscoe in treating neurodegeneration diseases (Li et al. 2022). They found five potential targets including COMT. COMT was also investigated as a therapeutic target to treat PD (Nissinen et al. 2005), schizophrenia, and cognitive impairment (O’Tuathaigh et al. 2012).

4.3 From Norepinephrine to Epinephrine

Catecholamine neurotransmitters such as dopamine, norepinephrine, and epinephrine play a key role in the function and regulation of the colorful expression of the human nervous system (Axelsson 1971; Fernstrom and Fernstrom 2007; Goldstein 2010). During biosynthesis, dopamine, norepinephrine, and adrenalin are produced by the same biochemical reacting chain, in which dopamine is converted to norepinephrine by dopamine beta-hydroxylase, and then the synthesis of epinephrine is catalyzed by phentolamine N-methyltransferase. This synthetic chain is also an important functional regulatory system for catecholamine neurotransmitters. It enables close interaction and balance among different neurotransmitters of dopamine, norepinephrine, and epinephrine so as to play their proper biological functions. It is of concern that the methyl donor properties of formaldehyde may directly affect the conversion from norepinephrine to epinephrine.

The key difference between norepinephrine and epinephrine is in the structure: the former has a hydrogen atom, whereas the latter contains a methyl group. The difference in structure gives them differences in function, which allows them to act in slightly different ways as they bind to receptors in the nervous system and muscles. In 1980s, the specific biochemical reaction equations related to the participation of formaldehyde in the conversion of norepinephrine to epinephrine were still not very clear. It was proposed that methanol could directly cause the expression changes in monoamines in the striatum and hypothalamus rather than through the metabolite formaldehyde (Jeganathan and Namasivayam 1987, 1988). Bao et al. (2007) demonstrated that the transmethylation of norepinephrine to form epinephrine was catalyzed by phenylethanolamine N-methyltransferase using S-adenosyl-L-methionine as the methyl donor (Bao et al. 2007). As shown in Fig. 3.2, the formation of S-adenosyl-L-methionine comes from a formaldehyde cycle (Tyihak et al. 1998). The cycle is a complicated process containing multiple chemical reactions including folate cycle (Bailey 1995), methionine cycle (Finkelstein and Mudd 1967), and other related pathways. Epinephrine can enhance memory consolidation in humans, particularly when combined with a certain level of arousal during encoding (Cahill and Alkire 2003). Another study conducted on rats found that adrenergic astrocytic signaling in the anterior cingulate cortex plays a fundamental role in modulating pain-related aversion (Iqbal et al. 2023).

Fig. 3.2

Diagram for formaldehyde cycle participating the methylation of norepinephrine to epinephrine. Conditions were similar to Fig. 3.1, except for formaldehyde cycle involved in the synthesis of epinephrine

5 Norepinephrine and Formaldehyde in Cellular Energy Metabolism

Norepinephrine (NE) also acts as a neuromodulator that regulates the activity of neuronal and non-neuronal cells in multiple ways, participating in cellular energy metabolism and the rapid modulation of cortical circuits (O’Donnell et al. 2012). Norepinephrine is required to promote wakefulness and for hypocretin-induced arousal in zebrafish (Singh et al. 2015), in which brain cellular energy metabolism should be enhanced. It is worth our attention that on the one hand, formaldehyde is toxic and induces cognitive impairment through multiple mechanisms, and that on the other hand, formaldehyde also affects cellular energy metabolism through different pathways. For example, human neuronal Tau acts in a chaperone-like manner toward several enzymes including D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12), lactate dehydrogenase (LDH, EC1.1.1.27), and glutamic dehydrogenase (GDH, EC 1.4.1.3). Tau prevents these proteins from misfolding and aggregation, assisting them in refolding to reach the native state. However, formaldehyde, the small aldehyde, can induce protein Tau dysfunction and aggregation (Luo and He 1999; Nie et al. 2007a). Aggregated Tau protein induced by formaldehyde not only loses the protective effect on the enzymes, but also becomes cytotoxic oligomers, leading to apoptosis of SH-SY5Y cells (Nie et al. 2007b). The misfolded Tau protein could induce protein conformational changes that inactivate GAPDH (Chen et al. 2000) and lactate dehydrogenase in solution (Tian et al. 2004).

As we know, lactic acid is one of the most important energetic metabolism compounds in the human brain, for instance, it is transported from astrocytes to neurons to serve as the primary energy substrate for neurons (Suzuki et al. 2011). Formaldehyde-induced lactic acid production and glutathione output stimulation in cultured neurons (Gray and Johnston 1987; Izumi and Zorumski 1999) suggest that formaldehyde may affect the basic neurotransmitter system through the lactic acid pathway. Lactate mediates glia-neuron signaling in mammalian brains and this association plays an important role in learning and memory (Luine and Hearns 1990). Astrocyte L-lactic acid signaling in the anterior cingulate cortex (ACC) modulates visceral pain aversion memory in rats (Francis et al. 2012). These data suggest that high formaldehyde levels and norepinephrine deficits both deteriorate cellular energetic metabolism and synaptic activities (Johnson et al. 2020).

6 Noradrenergic Locus Coeruleus and Neurodegenerative Diseases

The relationship between acetylcholinergic neuron and AD, as well as the relationship between dopaminergic neuron and PD, have been widely studied in the past and present. Recently, the contribution of noradrenergic dysfunction to the pathogenesis of AD and PD has become a central area of attention (Krohn et al. 2023). However, the noradrenergic locus coeruleus (LC) is among the earliest sites of Tau pathology in AD and alpha-synuclein pathology in PD, respectively (Singh 2020; Iannitelli et al. 2023). Though the extent of degeneration to the LC in healthy ageing remains unclear, a decrease in norepinephrine levels is in line with locus coeruleus cell loss in AD. The absence of statistical difference and an equal level of norepinephrine’s metabolites, for instance, 3-methoxy-4-hydroxyphenylglycol (MHPG), could indicate a compensatory mechanism (Moreira et al. 2023). The human data provided by pharmacoepidemiologic analyses and clinical trials together identify adrenoceptors as promising targets for the treatment of neurodegenerative diseases (Matt et al. 2023).

7 Prospective

An accumulation of endogenous formaldehyde has been found in the hippocampi of aged mice and rats, the senescence accelerated prone 8 (SAMP8) mice, APP and APP/PSI transgenic mice, and patients with AD (Tong et al. 2013b). Inhibiting FA-degrading enzymes or injecting excess FA directly causes deficits in LTP and memory in healthy adult rats (Tong et al. 2013a, b). The above findings indicate that while the concentrations of these two endogenous factors (either FA accumulation or NE deficiency) change in the opposite direction, both of them have a common destructive effect: the impairment of memory during aging.

Formaldehyde can directly react with the alpha-amino group of catecholamines, and indirectly affect the structure and function of dopamine, norepinephrine, and epinephrine through methylation and demethylation depending on the formaldehyde cycle (Li et al. 2022; Nygren 1976). On the other hand, under the action of demethylase (KDM1 and JmjC, etc.), demethylation occurs and releases formaldehyde (Walport et al. 2012; Pavlenko et al. 2022; Tong et al. 2013a, b; Zhai et al. 2018). For example, ribose-glycated BSA has high cytotoxicity (Xi et al. 2022), which can promote the release of formaldehyde from histone demethylation, resulting in a significant increase in the concentration of formaldehyde in cells and culture media (Tong et al. 2013a). Studies have shown that incubation with low concentration of formaldehyde is conducive to the survival of some cultured cells (Tong et al. 2011). Feeding with low concentration of formaldehyde can increase cell viability (Miao et al. 2013) and prolong the lifespan of fruit flies (Li and He 2016) (Chap. 15), while the effect of higher concentration of formaldehyde is reversed in the two experimental systems above. In the above experiments, formaldehyde may have played a different role by regulating methylation and hydroxymethylation. The function of catecholamines can be significantly influential through the direct action of formaldehyde or through methylation modification. In addition, formaldehyde is indirectly involved in the choline metabolic pathway, which is a key component in the synthesis of acetylcholine, as described by Pietzke and his colleagues (Pietzke et al. 2020). Therefore, the relationship between formaldehyde and catecholamines under physiological and pathological conditions deserves further attention and research.

Endogenous formaldehyde can be produced through oxidative stress and inflammation, such as the production of formaldehyde by monoamine compounds catalyzed by semicarbazide-sensitive amine oxidase (SSAO) (Yu et al. 2006; Chen et al. 2023). Mitochondria are considered the main organelles of formaldehyde production in cells (Xin et al. 2019; Tyihak et al. 1998). Electron leakage in the electron transport chain of mitochondria (Zhao et al. 2019; Rosa et al. 2023) is an important source of oxidative stress and free radicals, and also one of the mechanisms through which cells produce formaldehyde. Excessive formaldehyde accumulation existed in postmortem brain tissue samples of Alzheimer’s patients, and urinary formaldehyde concentration was elevated in patients with age-related intellectual disability (Crow 1968). Endogenous formaldehyde is accumulated in the hippocampal sites of Alzheimer’s disease patients and elderly animals. Injection of formaldehyde into the hippocampus can induce age-related spatial memory deficits and overall DNA methylation decline, and these experimental defects can be reversed by formaldehyde dehydrogenase (FDH) (He et al. 2017; Karuppagounder et al. 2009). It is worth noting that overexpression of the formaldehyde-metabolizing enzyme ADH5 causes cognitive impairment in Drosophila and mice (Mei et al. 2015; Zhang et al. 2017), suggesting that having too low a concentration of formaldehyde in the body can also be damaging.

Formaldehyde can affect norepinephrine and is definitely involved in multiple and complicated aspects. The locus coeruleus, which is the main source of norepinephrine in the brain, makes some of the most diffuse connections in the brain. Just one of its neurons can make more than 250,000 synapses, and it has one axon branch in the cerebral cortex and another in the cerebellar cortex. In this review, we draw attention to the mechanisms that underlie LC degeneration in ageing, AD, and PD. We aim to motivate future research to investigate how early degeneration of the catecholaminergic system may play a pivotal role in the pathogenesis of AD and PD, which may also be relevant to other neurodegenerative diseases (Krohn et al. 2023). The diverse symptomatology of PD and AD, which is not limited to cardinal motor and cognitive abnormalities, strongly suggests a multisystem neurodegenerative process. In this context, it is increasingly clear that the LC/NE system plays a key role in the initiation and maintenance of the neurodegenerative diseases (Malatt and Tagliati 2022).

Acknowledgement

All the grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_4

4. Formaldehyde Serves as a Key Factor in the (De)methylation for Memory Formation

Mengqi Xi¹, Tao Su², Ying Liu¹ and Rongqiao He2  

(1)

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China

(2)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

The methylation of DNA, RNA, and histone is a fundamental mechanism of epigenetic regulation, involving the addition of a methyl (CH₃) group to these biomolecules through the formaldehyde cycle. This process frequently alters gene function via chromatin remodeling. Methylation of DNA, RNA, and/or histone is regarded as a critical step in memory formation. As a methyl donor for the methylation of DNA, RNA, and histone, formaldehyde acts as an epigenetic factor participating in this reversible and dynamic methylation process. During DNA demethylation, formaldehyde is produced in both dividing cells and post-mitotic neurons. Notably, endogenous formaldehyde levels increase in aging populations, whereas DNA methylation may decrease. This correlation suggests a close link between learning-responsive DNA methylation and memory formation. Moreover, abnormal metabolism of endogenous formaldehyde, impacting DNA, RNA, and histone methylation, is implicated in age-related cognitive decline. The concentration of formaldehyde positively correlates with cognitive impairments, such as Alzheimer’s disease (AD) and post-stroke dementia (PSD). Dysregulation of DNA, RNA, and/or histone methylation disrupts adult hippocampal neurogenesis (AHN) and contributes to memory deficits in AD patients and mouse models. Circadian disruptions are common in AD patients, and the methylation of clock genes, such as PER1 and CRY1, is closely associated with memory loss. Hypermethylation of these clock gene promoters may contribute to cognitive dysfunction. In rats, enhancing DNA demethylation or inhibiting DNA re-methylation results in spatial memory deficits during memory formation. However, scavenging elevated formaldehyde levels effectively alleviates memory loss in rats. In this chapter, we delve into the role of endogenous formaldehyde in the methylation and demethylation of DNA, RNA, and histone, as well as its impact on memory formation and loss.

Keywords

FormaldehydeMethylationDemethylationDNARNAHistonesCircadian rhythmMemoryCognitive impairment

Abbreviation

Aβ1–40

Amyloid beta 1–40

AD

Alzheimer’s disease

ADH

Ethanol dehydrogenase

ALKBH5

alkB homolog 5

APP

Amyloid precursor protein

BACE

Beta-site amyloid precursor protein cleaving enzyme

BBB

Blood–brain barrier

BER

Base excision repair

BMAL1

Brain muscle aryl hydrocarbon receptor nuclear translocator-like 1

BSA

Bovine serum albumin

5-CaC

5’-Carboxylcytosine

CLOCK

Circadian locomotor output cycles Kaput

CpG

Dinucleotide

CRY

Cryptochrome

DNMT

DNA methyltransferase

FAD

Familial Alzheimer’s disease

FAD

Flavin adenine dinucleotide

5-FC

5-Formylcytosine

FDH

Formaldehyde dehydrogenase

FTO

Fat mass and obesity-associated gene

GSK-3β

Glycogen synthase kinase-3 beta

HDAC3

Histone deacetylase 3

5-HmC

5-Hydroxymethylcytosine

KDM1A

Lysine-specific demethylase 1

LSD1

Lysine-specific demethylase 1

LTM

Long-term memory

5mC

5-Methylcytosine

ME1

Monomethylated

ME2

Demethylated

ME2A

Asymmetrical dimethylation

ME2S

Symmetrical dimethylation

ME3

Trimethylated

MT-DNA

Mitochondrial DNA

NPAS2

Neuronal PAS domain protein 2

NSCs

Neural stem cells

2OG

2-Oxoglutarate

PER

Period

PS1

Presenilin 1

SAM

S-Adenosyl-L-methionine

SSAO

Semicarbazide-sensitive amine oxidase

STM

Short-term memory

TET

Ten-eleven translocated oncogene

THF

Tetrahydrofolic acid

1 Introduction

The incidence of Alzheimer's disease (AD) is escalating both globally and domestically, yet the underlying etiology and pathophysiology of this polygenic, non-communicable disorder remain poorly understood. Accumulated evidence suggests a link between lifestyle factors and the development of AD (Flicker 2010). Variables such as smoking, physical activity, education, social engagement, cognitive stimulation, and diet are purported to play a role in the onset and progression of AD (Song et al. 2022). These environmental factors, both in vitro and in vivo, may disrupt specific epigenetic mechanisms, promoting a reprogramming of gene transcription. Studies of simple organisms, like budding yeast, worms, and flies, indicate that the loss of epigenomic information could be a potential driver of aging in these species. Yang et al. have provided evidence that cellular responses to damage and the resultant loss of epigenetic information propel mammalian aging (Yang et al. 2024). Epigenetic mechanisms, such as DNA methylation, hydroxymethylation, regulation of miRNAs, long non-coding RNAs, and histone modifications, are known to be dysregulated in AD (Raval et al. 2023). Additionally, methylation of circRNA m6A may be implicated in AD pathogenesis (Zhang et al. 2023). Therefore, understanding the relationship between epigenetics and age-related cognitive impairment is crucial.In the central nervous system, the epigenetic marking of chromatin is deemed an essential mechanism for learning and memory. This mechanism enables nerve cells to respond to environmental stimuli, modulate their gene expression profiles, and establish and maintain their unique identities (Gräff et al. 2010). Epigenetic mechanisms, encompassing a diverse array of histone, DNA, and RNA modifications, specifically switch genes “on” or “off” without altering the nucleotide sequence (Berger et al. 2009). Methylation and demethylation of DNA (Bochtler et al. 2017), RNA (Dezi et al. 2016), and histone (Gupta et al. 2010) are involved in regulating various cellular processes, including genomic imprinting, chromatin conformation, transcription, chromosome stability, and embryonic development across all cell types (Bergman and Cedar 2013). However, epigenetic modifications can also have detrimental effects, such as promoting tumorigenesis (Maity et al. 2021). Unlike genetic changes, which are irreversible alterations of the DNA sequence, epigenetic changes are reversible and can be targeted by drugs to treat diseases associated with epigenetic imbalance (Hwang et al. 2017; Mirfattah et al. 2016). These functionally relevant changes are intimately linked to brain functions (Martinowich et al. 2003). The establishment of persistent epigenetic states in nerve cells is closely tied to neural plasticity and memory formation (Reik et al. 2001). Learning, a multifaceted process involving various proteins and epigenetic regulatory enzymes, induces DNA (de)methylation (Ooi and Bestor 2008). Recent studies have highlighted formaldehyde’s significant role in reversible and dynamic methylation of biomacromolecules (Bird 1992; Shi et al. 2004).

In our laboratory, Tong and his team have observed a close correlation between age-related cognitive impairment and endogenous formaldehyde metabolism and DNA methylation (Tong et al. 2012, 2013). Dysmetabolism of endogenous formaldehyde disrupts DNMT function, leading to memory loss in age-related cognitive impairment (Tong et al. 2013). Xi et al. reported a significant increase in formaldehyde levels in the medium of SH-SY5Y cells cultured with riboglycated bovine serum albumin (BSA), accompanied by histone demethylation (Xi et al. 2022). In light of its roles in epigenetic modification and regulation, formaldehyde can be classified as an epigenetic factor. This chapter delves into the fundamental insights regarding the function of endogenous formaldehyde in memory formation, cognitive ability, impairment, and neurodegenerative diseases.

2 Formaldehyde's Role in DNA Methylation and Demethylation Processes

The DNA methylation and demethylation phenomena are predominantly observed on CpG dinucleotides, commonly referred to as CpG islands, which occupy approximately 40% of gene promoters (Jabbari and Bernardi 2004). In contrast, methylation and demethylation events occurring at non-CpG dinucleotide positions are typically noted in embryonic stem cells (Abdelfatah et al. 2016; Li et al. 2016). Notably, over 75% of CpG sites are typically methylated in mammalian cells, yet global DNA methylation levels decrease with age, which may lead to transcriptional deregulation and adverse aging consequences (Unnikrishnan et al. 2018). 5-Methylcytosine (5mC) is pivotal in regulating gene expression, genomic imprinting, and transposable element suppression. Consequently, the most extensively studied DNA methylation process involves the covalent addition of a methyl group to the 5-carbon position of the cytosine ring, resulting in the formation of 5mC (Schübeler 2015). These methyl groups protrude into the major groove of DNA, thereby inhibiting transcription (Lister et al. 2009). In the methylation of DNA/RNA/histone, DNMT participates in the generation of 5mC in an enzymatic-activity-dependent manner, and uses S-adenosyl-L-methionine (SAM) as the methyl donor sourced from the body’s “one-carbon pool” (Crider et al. 2012; Yan and Fujimori 2011). Interestingly, formaldehyde also serves as a methyl donor through the formaldehyde cycle (Burgos-Barragan et al. 2017; Tyihák et al. 1998). Formaldehyde reacts with tetrahydrofolic acid (THF) to produce 5,10-methylene tetrahydrofolic acid (Morellato et al. 2021), which subsequently donates the methyl group for methionine formation via the formaldehyde cycle (Fig. 4.1).

Fig. 4.1

Diagram of DNA, RNA, and protein (histone) methylation through formaldehyde cycle. The formaldehyde cycle encompasses a series of intricate chemical reactions that particpates the methylation of biomarcomolecules such as DNA, RNA, and histones via the folate cycle, methionine cycle, and related biochemical pathways. This schematic diagram simplifies formaldehyde cycle, showing formaldehyde as a donor for the methylation in the reactions. SAH, S-adenosyl-L-homocysteine; SAM, S-adenosyl-L-methionine

The activity of DNA methyltransferase, particularly DNMT1, DNMT3a, and DNMT3b, primarily catalyzes the formation of methylated cytosines on CpG dinucleotides in vertebrates (Law and Jacobsen 2010; Ciccarone et al. 2018). Among these, DNMT1 is integral to the DNA replication complex, maintaining the methylated DNA levels during replication (Pollema-Mays et al. 2014). While present in both germ and somatic cells, DNMT1 cannot independently initiate methylation (Wang and Shen 2004). Conversely, DNMT3a and DNMT3b are predominantly expressed during early developmental stages and in embryonic stem cells, where they activate the DNA methylation process (Métivier et al. 2008). DNMT genes are indispensable for development, as their deletion can result in early embryonic lethality. Epigenetic research has demonstrated that formaldehyde can modulate the expression and activity of DNMTs (Bernardini et al. 2020). Furthermore, Tong et al. reported that the brain formaldehyde level influences DNMT activity and the extent of DNA methylation (Tong et al. 2013).

Formaldehyde plays a dual role in DNA methylation dynamics, functioning not only as a methyl donor during the DNA methylation process but also as a byproduct of DNA demethylation, as reported by Kress et al. (2001). The biochemical pathways underlying demethylation encompass both passive and active mechanisms, as detailed by Bochtler et al. (2017). Passive demethylation, specifically targeting the conserved CpG dinucleotide methylation pattern, occurs when DNA replication diverges from the maintenance of methylation. This non-catalytic process results in the gradual removal of 5-methylcytosine (5mC) during cellular replication cycles (Clark 2015). The suppression of DNMT1 activity by chromatin structure and transcription complex post-replication further contributes to reduced DNA methylation levels. The demethylation of deoxycytidine and 5-azacytidine simply arises from the absence of methylation maintenance post-replication, leading to endogenous formaldehyde formation (Venturelli et al. 2013). This passive process operates independently of demethylating enzymes. With advancing age, a decline in DNA methylation is observed, and accumulation of endogenous formaldehyde may occur in individuals with formaldehyde metabolism dysregulation.

Conversely, active demethylation involves a complex interplay of various enzymes, encompassing direct demethylation, nucleotide excision repair (NER), base excision repair (BER), 5mC deamination-dependent BER, 5mC oxidative demethylation, elongator complex protein 3, and catalyzed 5mC demethylation (Niehrs 2009; Wu and Zhang 2010). Unlike passive demethylation, which is replication dependent, active demethylation is accompanied by formaldehyde formation. Intriguingly, Wit et al. (2023) identified histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production, with mitochondrial complex I serving as a mediator in HDAC3 regulation (deacetylase activity). Metabolic profiling reveals that this mitochondrial requirement is distinct from energy generation for formaldehyde detoxification, indicating that complex I and HDAC3 jointly modulate the abundance of this ubiquitous genotoxic metabolite.

The modification of 5mC encompasses deamination, methyl dehydrogenation, and oxidative demethylation (Tohgi et al. 1999). The active demethylation process involves iterative oxidative steps that catalyze the replacement of 5mC with cytosine (Smith and Meissner 2013). This cascade of reactions is orchestrated by a suite of enzymes known as ten-eleven translocation (TET) dioxygenases (Ciccarone et al. 2018), including TET1, TET2, and TET3, which primarily participate in oxidative demethylation (Wu and Zhang 2011). TET enzymes, which are dependent on 2-oxoglutarate (2OG) and Fe²⁺, catalyze the conversion of 5mC into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) through three consecutive oxidation reactions in cultured cells (Wu and Ling 2014). Subsequent decarboxylation of 5caC leads to its conversion back to cytosine. The functional roles of the intermediates in DNA demethylation within epigenetic control remain an area of ongoing research (Elliott et al. 2015). Endogenous formaldehyde is produced during the oxidative demethylation of 5fC to cytosine. Additionally, the oxidative methyl group of cytosine can undergo demethylation via the BER pathway facilitated by glucosyltransferase, yielding endogenous formaldehyde and cytosine (Su et al. 2015).

3 Formaldehyde and RNA Methylation/Demethylation

RNA fulfills a dual role in biological systems: it not only serves as the conduit for genetic information from DNA to protein but also acts as a regulator of diverse biological processes. The reversible RNA modifications play crucial roles in the posttranscriptional regulation of gene expression. Notably, N6-Methyladenosine (m6A) stands out as the most prevalent modification found in mRNAs and long noncoding RNAs (lncRNAs) including ribosomal RNA (rRNA), small nuclear RNA (snRNA), and tRNA in the eukaryotes (Wang and He 2014). Several lncRNAs harbor m6A, suggesting that specific ncRNAs transcribed by RNA polymerase II are also susceptible to m6A methylation. In 2011, groundbreaking research revealed that mRNA methylation plays a pivotal role in maintaining human energy homeostasis (Jia et al. 2011). The enzymes involved in m6A modification are categorized as “writers” (which catalyze the chemical modification at specific sites), “erasers” (which remove the modifications), and “readers” (which recognize the modified sites in DNA or histones). To date, m6A modification is the only RNA modification for which enzymes involved in all three of these distinct steps have been identified (Esteve-Puig et al. 2020). Analogous to the process of active DNA demethylation, the balance of reversible RNA demethylation necessitates several crucial RNA demethylases, including fat mass and obesity-associated gene (FTO) and AlkB homolog 5 (ALKBH5) (Meyer et al. 2012). Both FTO and ALKBH5 belong to the α-ketoglutarate and Fe2+-dependent AlkB family of proteins that catalyze oxidative demethylation (Sanchez-Pulido and Andrade-Navarro 2007). However, they produce different major products: N6-hydroxymethyladenosine (hm6A) and adenosine, respectively (Toh et al. 2020). M6A on nuclear RNA, encompassing mRNA, lncRNA, and other RNA types, serves as the primary substrate for FTO (Zheng et al. 2013). In contrast to FTO, which follows a traditional oxidative N-demethylation pathway to convert m6A to hm6A, with subsequent slow release of adenosine and formaldehyde, ALKBH5 catalyzes a direct transformation of m6A to adenosine, accompanied by rapid formaldehyde release (Toh et al. 2020).Mutations in both FTO and ALKBH5 exhibit noticeable phenotypes, underscoring the functional significance of reversible m6A methylation on RNA. The FTO gene is linked to body mass index and predisposes individuals to obesity and type 2 diabetes (Ding et al. 2023; Field et al. 2007; Frayling et al. 2007). Additionally, FTO is highly expressed in the human brain and is associated with cognitive changes in prospective cohort studies (Bressler et al. 2012). ALKBH5 efficiently catalyzes the fragmentation of its proposed nascent hemiaminal intermediate, yielding formaldehyde and a demethylated nucleoside (Kaur et al. 2022). ALKBH5 plays a vital role in meiosis, and mice lacking ALKBH5 are infertile (Klungland and Dahl 2014). However, further research is needed to elucidate the detailed mechanisms underlying demethylation-induced endogenous formaldehyde production and its role in cognitive impairment..

4 Formaldehyde and Histone Methylation/Demethylation

Histone modifications are believed to play a role in regulating gene expression by modulating chromatin compaction or interactions with other protein complexes. Reversible histone methylation and demethylation are crucial for orchestrating chromatin dynamics, gene expression, and transcription processes (Cheung et al. 2010; Janardhan et al. 2018). This methylation occurs on three fundamental amino acid residues: arginine, lysine, and histidine (Borde et al. 2009). Specifically, arginine residues can undergo mono- (me1) and di- (me2) methylation on their guanidinyl groups, with di-methylation occurring either symmetrically (me2s) or asymmetrically (me2a) (Wang et al. 2022a). In contrast, lysine residues can be mono-, di-, or tri-methylated on their ε-amine groups (De Santa et al. 2007; Janardhan et al. 2018). The methylation of lysine and arginine residues in histones (H3/H4) is catalyzed by methylases, using the methyl group derived from S-adenosylmethionine (SAM), which is supported by formaldehyde (Pedersen and Helin 2010). Conversely, methylated histones can be demethylated by demethylases, releasing formaldehyde in the process and participating in the “one-carbon pool” metabolic cycle (Shi et al. 2004). The reversible methylation cycle of histones encompasses formaldehyde, SAM, and the histone itself (Luka et al. 2014).The most extensively studied histone methylation sites include histone H3 lysine 4 (H3K4), H3K9, H3K27, H3K36, H3K79, and H4K20 (Sun et al. 2014). The discovery of lysine-specific demethylase 1A (KDM1A), an H3K4 demethylase, demonstrated the reversibility of histone methylation. To date, two protein families have been identified as possessing lysine demethylase activity. One family consists of amine oxidases that catalyze the demethylation of mono- and di-methylated lysine residues using flavin adenine dinucleotide (FAD) as a cofactor. The other family, the JmjC proteins, catalyzes oxidative demethylation reactions with iron and α-ketoglutarate serving as cofactors (Janardhan et al. 2018). This JmjC family encompasses KDM1, KDM2, KDM3, KDM4, KDM5, and KDM6 (Cheng et al. 2014; Kumarasinghe and Woster 2014; Pedersen and Helin 2010; Zhang et al. 2014). The specific locations of N-methylated histones and the amount of methylation catalyzed by KDM enzymes result in diverse epigenetic effects (Li et al. 2021). For instance, methylation at H3K4, H3K36, and H3K79 promotes transcription, whereas methylation at H3K9, H3K27, and H4K20 is associated with transcriptional repression (Sun et al. 2014; Wang et al. 2022a).

Lysine-specific demethylase 1 (LSD1), a member of the FAD-dependent amine oxidase family, demethylates mono- and di-methylated H3K4 and H3K9. This demethylation process results in the hydrolysis of methylated residues to produce formaldehyde and other aldehydes through a nonenzymatic pathway (Neelamegam et al. 2012). Similarly, semicarbazide-sensitive amine oxidase (SSAO) catalyzes the conversion of methylamine to formaldehyde, using the same cofactor (FAD) and mechanism as LSD1 for cleaving inactivated carbon-nitrogen bonds from their respective substrates (Zhou et al. 2015). As detailed by Shi et al. (2004), LSD1 can catalyze the conversion of one molecule of H3K4 to non-methylated H3K4, accompanied by the release of two molecules of formaldehyde (Li et al. 2021) (Fig. 4.2). Our experimental results also indicate that upregulation of LSD1 in SH-SY5Y cells is accompanied with a significant increase in formaldehyde levels in cell cultures (Xi et al. 2022). Lysine of me1 and me2 can be methylated, because the oxidation of methylated amine needs at least one proton (Zhou et al. 2015). During a complete catalytic cycle, the cofactor FAD is first reduced to FADH2 and then is likely to be reoxidized by oxygen, producing hydrogen peroxide and formaldehyde. Another class of lysine demethylases, those containing the JmjC-domain, use iron and α-ketoglutarate as cofactors. These enzymes catalyze the demethylation of lysine, resulting in the release of succinate, carbon dioxide, formaldehyde, and demethylated lysine (Janardhan et al. 2018).

Fig. 4.2

Diagram of histone K4H3me2 demethylation in the presence of LSD1. The demethylation of histone K4H3me2 produces 2 moles of hydrogen peroxide and 2 moles of formaldehyde, respectively

The methylation and demethylation of DNA, RNA, and histone play crucial roles in various processes in mammals, including development, behavior, cognition, and more (Klose and Zhang 2007; Maity et al. 2021; Smith and Meissner 2013). Dysfunction in these reversible methylation processes is implicated in numerous diseases, such as cancer, developmental malformations, and cognitive impairments (Hwang et al. 2017; Wang et al. 2016). Excess endogenous formaldehyde has also been identified as a significant risk factor for cancer and cognitive dysfunction (He et al. 2010). Formaldehyde participates in the reversible methylation of DNA, RNA, and histone, regulating epigenetic memory in processes such as chromosome segregation, transcriptional regulation, and DNA repair. Considering that DNA methylation is a key factor in memory formation in mammals, formaldehyde can influence the learning and memory process. Previous studies have reported that excess formaldehyde in the brain inhibits DNMT activities, leading to decreased levels of DNA methylation (Liu et al. 2011; Tong et al. 2015).

Epigenetic regulations, encompassing chromatin modification, DNA methylation, and alterations in regulatory RNAs (such as miRNAs), exert profound influences on both memory function and neurodegenerative processes (Ghosh and Saadat 2023). Notably, methylation can regulate the roles of miRNAs (Wong et al. 2011). According to Kumari et al. (2021), variations in m6A RNA modification, including those affecting miRNAs, may be implicated in disease pathogenesis and contribute to metabolic memory phenomena. Recent years have witnessed a surge in studies demonstrating the significant role of miRNAs in the progression of numerous neurodegenerative disorders. For example, miRNA dysregulation has been linked to the advancement of AD, as reported by Rahman et al. (2020). Specifically, MiR-351-5p emerges as a pathogenic factor in hippocampal neural progenitor cells, showing heightened expression in AD patients (Woo et al. 2020). Conversely, MiR-132 consistently undergoes downregulation during AD progression. Importantly, as described by Walgrave et al. (2021), restoring miR-132 levels in the hippocampus of AD mouse models can ameliorate adult hippocampal neurogenesis (AHN) and associated memory impairments.

Formaldehyde, an intermediate metabolite of methanol metabolism, is produced by the catalysis of methanol via ethanol dehydrogenase (ADH) and further oxidized to formic acid by formaldehyde dehydrogenase (FDH), as outlined by Staab et al. (2009). Studies using transgenic models with FDH knockdown have revealed spatial learning and memory impairments in rats compared to control groups (Qiang et al. 2014; Wu et al. 2014). As a small molecule, formaldehyde readily crosses the blood–brain barrier (BBB), as demonstrated by Shcherbakova et al. (1986). The capacity for formaldehyde metabolism diminishes with age (Tong et al. 2013), and endogenous formaldehyde levels inversely correlate with general cognitive abilities (Tong et al. 2017; Yu et al. 2014). Accumulation of formaldehyde in the central nervous system may lead to brain damage and cognitive decline.

The reversible methylation of DNA, RNA, and histone is a potential source of endogenous formaldehyde in the body. In turn, formaldehyde acts as a methyl donor in epigenetic modifications, as suggested by Bou-Nader et al. (2021). The critical role of endogenous formaldehyde in reversible methylation processes and the mechanisms underlying its impact on cognitive function necessitate further investigation.

5 Memory Is Associated with Methylation and Demethylation

In 1969, Griffith and Mahler introduced the DNA ticketing theory of memory, proposing that DNA functions as a lifelong information storage molecule (Griffith and Mahler 1969). Subsequently, Crick hypothesized that memory could be encoded through reversible modifications to DNA and proteins by specific enzymes (Crick 1984), with DNA methyltransferase emerging as a key candidate for this role. Holliday et al. indicated the significance of cytosine methylation in DNA for memory formation (Holliday 1999). Memory is categorized into short-term memory (STM) and long-term memory (LTM), based on the duration of information retention. STM formation typically involves the modification of existing synapses without altering protein expression, as previously reported (Fiumara et al. 2007). Conversely, LTM formation necessitates the activation and inactivation of transcription factors, triggering intricate synapse-to-nuclear signaling cascades that result in stable changes in gene expression (Alece Arantes Moreno et al. 2023; Heyward and Sweatt 2015; Morris and Monteggia 2014).

AD, a chronic neurodegenerative disease, accounts for 60–70% of dementia cases. AD is characterized by memory loss and has a polygenic etiology (Lippa 1999). Genetic studies have linked mutations in presenilin 1 (PS1) and amyloid precursor protein (APP) to early-onset familial Alzheimer’s disease (FAD) (Hsiao et al. 1996). However, the majority of AD cases are sporadic, with polygenic risk factors (Roger et al. 1995). Pollwein et al. discovered that APP expression is regulated by its CpG island-rich promoter (Pollwein et al. 1992). The Methylations of upstream Promoters element of the APP gene was observed with exhibits high tissue specificity (Rogaev et al. 1994). Notably, Wei et al. found that the APP gene was the only one that undergoes consistent hypermethylation in both the brain and peripheral blood (Wei et al. 2020). Moreover, APP promoter methylation is highly correlated with age (Tohgi et al. 1999). Female rats exhibit lower APP mRNA levels in the brain compared to male rats (Mani and Thakur 2006). APP/PS1 transgenic mice show elevated mRNA methylation in the cortex and hippocampus (Han et al. 2020). In these mice, mitochondrial DNA (mtDNA) methylation decreases in the D-loop region but increases in the 12S rRNA gene of the hippocampus (Xu et al. 2019). Beyond APP, other genes such as the beta-site amyloid precursor protein cleaving enzyme (BACE) and PS1 are also implicated in DNA methylation processes (Fuso et al. 2005).

To date, extensive research has been conducted to elucidate the intricate relationship between (de)methylation and memory formation, as evidenced by numerous studies (Jarome and Lubin 2014; Maity et al. 2021). DNA or histone methylation, a stable epigenetic modification crucial for regulating transcription, transposon imprinting and silencing, plays a pivotal role in memory formation and maintenance, particularly during synapse development (Collins et al. 2019; Dias et al. 2015; Poon et al. 2020). Heyward and Sweatt have notably emphasized the hypothesis on the role of epigenetics in memory processes (Heyward and Sweatt 2015). Within this framework, methylation-driven alterations in gene expression are categorized as either permissive for memory (memory promoters) or disruptive (memory suppressors), a concept that has been long-standing in the field (Lister and Mukamel 2015). Lister and Mukamel further suggested that the dynamics of DNA methylation in the brain are essential for human learning and memory, with distinct spatio-temporal characteristics potentially facilitating specific permissive or instructive roles in cognitive functions. DNA methyltransferases are indispensable in the process of DNA methylation and, consequently, in learning and memory (Cui and Xu 2018; Morris and Monteggia 2014). Recognizing formaldehyde‘s role in both methylation and demethylation, we have conducted studies to investigate its impact on memory and the function of DNMT (Tong et al. 2013). Notably, Barbosa et al. reported that even minimal exposure to formaldehyde can disrupt DNA methylation, leading to epigenetic alterations associated with cancer development (Barbosa et al. 2019).

Moreover, the regulation of chromatin structure through posttranslational modifications of histone proteins, particularly histone H3 phosphorylation and acetylation, marks a crucial early stage in synaptic plasticity and the formation of long-term memory (Ng et al. 2003; Sims et al. 2003). Specifically, the regulation of H3K4 methylation, often considered a marker of transcriptional activation, has been implicated in both hippocampus- and striatum-dependent memory formation in mice. Mutations in genes encoding H3K4 methylation modifiers have been linked to cognitive dysfunction in humans (Collins et al. 2019). Gupta et al. observed an upregulation of trimethylation of histone H3 at lysine 4 (H3K4) in the hippocampus 1 h after contextual fear conditioning, suggesting that histone methylation is actively regulated in this brain region and facilitates long-term memory formation (Gupta et al. 2010). Fortress et al. provided initial evidence that histone modifications and DNA methylation play essential roles in estrogen-regulated memory processes (Fortress and Frick 2014). Despite the extensive focus on the link between epigenetics and memory, and the efforts to decipher the various mechanisms underlying methylation and demethylation in memory formation and suppression, there is a notable lack of research exploring the origins and destinations of methyl groups and the impact of formaldehyde, a product of methyl group release, on cognitive function and impairment in vivo. Formaldehyde serves as both a donor and a participant in methylation and demethylation reactions. Therefore, it is imperative to delve deeper into this area of study as it holds the potential to unlock new insights into the complex interplay between epigenetic modifications and cognitive processes.

6 Formaldehyde, an Epigenetic Factor in Memory Formation and Loss

Formaldehyde, functioning as a methyl group donor, participates in the modification of DNA and histone. Specifically, cytosine methylation of genomic DNA diminishes with age across various mammalian tissues, as noted by Qazi et al. (2018). Conversely, endogenous formaldehyde levels escalate with advancing age, as reported by Tong et al. (2012), potentially stemming from the demethylation of DNA, RNA, and histones. The involvement of epigenetic factors, particularly formaldehyde, in the development of neurodegenerative disorders associated with aging warrants further attention. Indeed, formaldehyde is implicated in diverse epigenetic mechanisms, including DNA and histone (de)methylation, in AD (Tong et al. 2013). This suggests that disruptions in formaldehyde metabolism may interfere with DNA and histone methylation and demethylation processes, potentially serving as a risk factor for age-related cognitive impairment, including memory loss.To delve into the intrinsic connection between endogenous formaldehyde and learning-responsive DNA methylation, as well as memory formation, Tong et al. conducted a study on Sprague-Dawley rats involved in spatial learning tasks. They observed that spatial learning triggers an initial global DNA demethylation, followed by subsequent re-methylation accompanied by an elevation in hippocampal formaldehyde levels, which then revert to the baseline (Tong et al. 2013). Notably, intrahippocampal injection of excess formaldehyde in normal adult rats mimicked the global DNA methylation decline associated with age-related spatial memory deficits. Further experiments, involving formaldehyde scavenging with FDH, enhancement of DNA demethylation through a DNA-demethylating agent, or inhibition of DNA re-methylation using 5-aza-2′-deoxycytidine, a DNA-demethylating agent by inhibiting DNMT activity (Hamm et al. 2009; Yamagata et al. 2012) in rats, all resulted in spatial memory defects during memory formation. These findings hint at a potential contribution of aging-related formaldehyde excess to cognitive decline.

DNMT enzymes play a role in memory formation by regulating DNA methylation (Cui and Xu 2018; Day and Sweatt 2010; Levenson 2006). Reduction in global DNA methylation by simultaneous knockout of DNMT1 and DNMT3a results in deficits in both memory acquisition and retrieval in mice (Feng et al. 2010; Miller et al. 2010; Sun et al. 2020). Conditional deletion of DNMT3b in a specific sub-region of the hippocampus impairs recognition memory in mice (Kong et al. 2020). Memory reconsolidation for a cocaine-paired stimulus critically depends on DNMT activity in the bilateral intra-basolateral amygdala (Shi et al. 2015). Neonatal sevoflurane exposure-induced cognitive impairments are associated with increased DNMT activity, which can be reversed by the DNMT inhibitor 5-aza-2′-deoxycytidine (Ju et al. 2016). Conversely, overexpression of DNMT3a in the hippocampus reverses spatial memory deficits in aged mice (Su and Tsai 2012). However, activity and expression of DNMTs, along with global DNA methylation levels, decrease in the brains of aged mice, aged rats, and autopsied brains of AD patients. Notably, hippocampus-related topographic amnesia is a common symptom of memory disorders in AD patients. Therefore, the misregulated DNMT function, coupled with defects in global DNA methylation, may underlie hippocampus-related spatial memory deficits.

Given that endogenous formaldehyde is involved in global DNA methylation and demethylation, Tong et al. investigated its relationship with DNMT activity to understand experience-mediated DNA methylation, which is essential for the recent memory formation and the remote memory maintenance. They found a significant increase in endogenous formaldehyde levels accompanied by a decline in global DNA methylation in the autopsied hippocampi of AD patients. Excess formaldehyde disrupts DNMT activities, leading to reduced DNA methylation, both in vitro and in vivo. Intrahippocampal injection of excess formaldehyde in healthy adult rats before spatial learning caused learning difficulties similar to those observed in patients at an early stage of age-related cognitive impairment (Tong et al. 2015). Injection after learning resulted in the loss of remote spatial memory, mimicking the late stage of AD. These findings support the hypothesis that aging-associated formaldehyde contributes to topographic amnesia in age-related cognition-impaired patients through DNA methylation and demethylation. Whether formaldehyde, which is also associated with histone methylation and demethylation, directly or indirectly affects learning and memory remains to be explored further.

Advanced glycation end products (AGEs) can be found in food or produced endogenously in biological systems (Kuzan 2021). AGEs participate in the pathological mechanisms underlying several diseases, including AD and multiple sclerosis (Chrysanthou et al. 2022). Glycated BSA by ribose reduces H3K4 methylation in SH-SY5Y cells (Xi et al. 2022). The promoter hypomethylation of the receptor for AGE (RAGE) was detected in diabetic retinopathy patients, suggesting that RAGE gene promoter methylation could inhibit retinal inflammation (Kan et al. 2018). DNA methylations and initiated demethylations of neuronal DNA cytosines, which alter gene expression, are fundamental to long-term memory formation (Bernstein 2022). In old rats, the methylation levels of CpG proximal to transcription factors associated with specific genes showed a significant correlation with spatial memory performance (Chiavellini et al. 2022).

7 Memory Associated with AHN and Circadian Alterations

Rigorous investigations into postmortem brains of AD patients and transgenic AD mouse models have consistently demonstrated that the accumulation of plaques and fibrillary tangles within the hippocampus is intricately linked to cognitive decline (Rahman et al. 2020). Unlike other brain regions, the adult mammalian hippocampus harbors neural stem cells (NSCs), capable of generating new neurons—a process termed adult hippocampal neurogenesis (AHN) (Babcock et al. 2021). Sustained AHN in adults is pivotal for neuronal plasticity, learning, memory retention, and emotion regulation (Kempermann et al. 2018). Among the pathological hallmarks of AD, the disruption of epigenetic mechanisms in NSCs fosters the generation of damaged neurons, exacerbating neuronal loss and impairing learning and memory functions. Research has shown that the IL-6/JAK2/STAT3 signaling pathway can modulate neurogenesis by upregulating DNMT1 in NSCs, facilitating DNA demethylation to regulate NSC status at the epigenetic level, and subsequently influencing AHN (Kong et al. 2019). Furthermore, mitochondrial dysfunction in neural progenitor cells leads to the degradation of lysine demethylase 5A (KDM5A), contributing to AHN deficiencies (Kim et al. 2022a, b). This may stem from the reduced transcription of BDNF due to decreased KDM5A expression, impeding neural differentiation and causing memory impairments. Circadian disruptions are common in AD patients and may exacerbate cognitive decline, neurodegeneration, and behavioral disturbances (Cronin et al. 2017). In mammalian cells, circadian rhythms are orchestrated by the transcriptional/translational oscillation of core clock components, including positive regulators such as BMAL1, CLOCK, and NPAS2, and negative regulators like CRY1/2 and PER1/2/3 (Jesse et al. 2024). Epigenetic control plays a crucial role in coordinating these transcriptional circadian oscillations, primarily through chromatin remodeling (Samoilova et al. 2021). Several studies have established a close association between DNA methylation of clock genes and cognitive impairment, with increased promoter methylation of the PER1 gene, and hypermethylation of the PER1 and CRY1 gene promoters observed in patients with cognitive dysfunction (Cronin et al. 2017; Kim et al. 2022a; Kim et al. 2022b; Xu et al. 2023).

Histone methyltransferase catalyzes the methylation of histone using SAM as a donor of the methyl group, and the demethylase erases the methyl group from histone. Thus, the SAM/SAH ratio is involved in circadian rhythms, and related with formaldehyde metabolism (González-Suárez and Aguilar-Arnal 2024). Fu et al. (2022) provided evidence that the SAM/SAH ratio can be used to facilitate early identification and the progression of risk prevention strategies for MCI in elderly. Additionally, a notable decrease in melatonin levels has been reported in the cerebrospinal fluid of post-mortem AD patients (Liu et al. 1999). Formaldehyde can directly inactivate melatonin and induce severe oxidative stress by lowering glutathione levels, thereby linking formaldehyde to AD through oxidative stress mechanisms (Mei et al. 2016). As the research community expands its focus on this field, it is anticipated that the epigenetic mechanisms underlying memory formation will be increasingly elucidated in the future.

8 Conclusion

DNA methylation, histone methylation, and histone acetylation are pivotal epigenetic processes integral to memory regulation. Chromatin remodeling, facilitated by epigenetic controls like methylation and demethylation of DNA, RNA, or histone, is considered a crucial mechanism underlying learning, memory, and long-term memory storage. Within these methylation and demethylation processes, endogenous formaldehyde is hypothesized to function as an epigenetic factor influencing memory formation or loss (Su et al. 2015). This hypothesis finds support in the following observations:

1.

Endogenous formaldehyde has been implicated in DNA and histone methylation processes (Li et al. 2021; Su et al. 2015).

2.

Formaldehyde participates in the demethylation and methylation cycles of DNA or histone, with demethylation accompanied by the release of formaldehyde (Shi et al. 2004). Notably, DNA demethylation triggers formaldehyde generation in both dividing cells and post-mitotic neurons (Tong et al. 2012).

3.

Endogenous formaldehyde levels increase with aging and positively correlate with cognitive impairments, such as AD and post-stroke dementia (Tong et al. 2009, 2012, 2017).

4.

Urine formaldehyde levels exhibit a detectable correlation with cognitive abilities in AD patients (Wang et al. 2022b).

5.

A systematic evaluation has identified urinary formic acid as a potential new biomarker for AD (Wang et al. 2022c).

6.

In rats, enhancing DNA demethylation or blocking DNA re-methylation through the use of 5-aza-2-deoxycytidine results in spatial memory deficits during memory formation (Tong et al. 2011).

7.

Changes in formaldehyde levels are associated with the expression and activity of DNMTs, both in vivo and in vitro (Tong et al. 2015).

8.

High concentrations of formaldehyde inhibit the NMDA receptor, impairing learning and memory in rats (Taylor et al. 2014; Yu et al. 2011).

9.

Epigenetic mechanisms play a role in the pathologies of neurological disorders, contributing to memory-related symptoms (Kim and Kaang 2017; Maity et al. 2021). Formaldehyde may be related to the disturbance of circadian rhythm in Alzheimer’s disease depended on the SAM/SAH ratio (Li et al. 2021; González-Suárez and Aguilar-Arnal 2024).

10.

Studies have demonstrated a correlation between abnormalities in m6A mRNA methylation, and the occurrence and progression of AD (Han et al. 2020; Ni et al. 2023; Shafik et al. 2021).

11.

The m6A methylation process is facilitated by the binding protein YTH N6-methyladenosine RNA binding protein 1, which promotes learning and memory formation in the hippocampus of mice (Shi et al. 2018).

12.

Altered m6A RNA methylation contributes to hippocampal memory deficits in mice (Pupak et al. 2022).

Methylation of DNA, RNA, and/or histone stands as a critical step in memory formation (Gupta et al. 2010; Maity et al. 2021). Collectively, these findings suggest that maintaining the homeostasis of endogenous formaldehyde metabolism is beneficial for cognitive behaviors. Conversely, formaldehyde dysmetabolism may disrupt the modifications of DNA, RNA, and histone, ultimately leading to memory loss. Future research should delve into the genes regulated by formaldehyde’s influence on methylation and demethylation processes, how these genes impact cognitive ability, and the underlying biological mechanisms involved.

Acknowledgement

All the grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_5

5. Dehydration, Formaldehyde, and Age-Related Cognitive Impairment

Ting Li¹ and Rongqiao He2  

(1)

Bayannur Hospital, Bayannur, China

(2)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Alzheimer’s patients look thin. In fact, it may not be thin; it is caused by long-term chronic dehydration. It has been known that chronic dehydration causes not only serum hyperosmotic pressure increase but also dysfunction in water, salt, and electrolyte metabolism, as well as acid-base balance in the central nervous system (CNS), resulting in cognitive impairment. Recently, an imbalance in the anabolism and catabolism of endogenous formaldehyde was considered as one of the risk factors involving age-related cognitive impairment. The levels of endogenous formaldehyde in inpatients were markedly higher than those in the age-matched participants. Thus, we are concerned about the relationship between cognitive impairment and water intake behavior, as well as that between dehydration and dysmetabolism of endogenous formaldehyde with aging. As a result of aging, serum arginine vasopressin (AVP) concentration and brain endogenous formaldehyde levels increase. Underwater deprivation, formaldehyde increased in the brains of C57BL/6j mice. An increase in urine formaldehyde was observed by water deprivation of university students from morning to lunchtime (5–6 h). Excess formaldehyde could activate ANG II to promote AVP expression. Meanwhile, the elevation of AVP activates semicarbazide-sensitive amine oxidase (SSAO) to produce more endogenous formaldehyde. Chronic hypertonic dehydration affecting learning with emotion may result from decreased serotonin by SSAO deamination in the mouse brain. These pathways could create a vicious cycle that worsens drinking behavior and reduces the frequency and amount of water intake. That is, at least, dysregulation of endogenous formaldehyde can affect water intake behavior. The highest concentration of endogenous formaldehyde is found in the morning, followed by a decrease around noon and an increase in the evening. Therefore, regular water intake including tea is recommended to intervene and reduce formaldehyde accumulation in the human body, especially when it is taken in the morning.

Keywords

DehydrationThirstSensationRespondCognitive impairment

Abbreviations

A

AD

Alzheimer’s disease

ADH3

Formaldehyde dehydrogenase 3

ALD

Aldosterone

ANG II

Angiotensin II

AVP

Arginine vasopressin

C

CNA

China Nutrition Association

D

DA

Dopamine

G

GSK-3β

Glycogen synthase kinase-3β

H

5-HT

5-Hydroxltryptamine

M

MMSE

Mini-Mental State Examination

MoCA

Montreal Cognitive Assessment

S

SAMP8

Senescence-prone strain 8

SAMR1

Senescence-resistant strain 1

SPs

Senile plaques

T

TH

Tyrosine hydroxylase

V

VD

Vascular dementia

1 Introduction

According to Thales (636–546 B.C.), everything arises out of water and returns to it (Thomson 1959). Living things arose in the water, and each human individual starts his/her life in a watery environment in utero. As described by Lao Zi (571–471 B.C.), a philosopher in ancient China: “Water benefits all living things but not for its own honor and profit.” However, humans have to carry the watery environment inside their bodies while living on land. Water is essential for survival and is used by the body each day (Yamada et al. 2022). Water is the basic and indispensable molecule for every activity of human cells. Therefore, the aqueous environment is essential for both intracellular and intercellular biochemical and physiological reactions. Water is central to maintaining the most important processes in the human body, such as circulation (blood and lymph), flow of cerebral spinal fluid (CSF), removal of soluble waste products, facilitating ingestion and digestion, and flushing out the urinary tract and other crucial organs (Hooper et al. 2014). Death could occur in the absence of fluid intake or serious dehydration far more quickly than due to lack of any other nutrient. Thus, it is emphasized that proper nutrition and hydration are a human right, especially for older patients (Beck and Volkert 2023).

Water is not only the most important solvent but also reacts with other compounds in the human body. For instance, after H₂O has got a carbon atom and is converted into CH₂O, it becomes seriously toxic. But in fact, we carry formaldehyde in the watery environment inside our body. Formaldehyde is involved in many aspects of biochemical pathways. The balance of anabolism and metabolism of endogenous formaldehyde is maintained by regulating systems. Many colleagues were recruited into the project to study the dangers of formaldehyde to human health. However, the relationship between dehydration and dysmetabolism of endogenous formaldehyde involved in age-related cognitive impairment needs further investigation although numerous studies have been carried out in recent years (Białecka-Dębek and Pietruszka 2019; Bethancourt et al. 2020; Alsanie et al. 2022). Thus, we would like to review the relation of formaldehyde with dehydration and cognitive impairment in this chapter.

2 Aging with Chronic dehydration 

Over 2000 years ago, Aristotle said: “Old age is dry and cold” (Aristotle 350 B.C. (n.d.)). The Chinese traditional medicine (Plain Questions, published 99–26 B.C.) described (Hou 2009): “Kidney essence withered first, accompanied by weakness of the spleen and the stomach, leading to disability of body fluid processing.” In other words, loss of interstitial fluid related to an imbalance of water homeostasis had been noticed in the far ancient period. Humans consume adequate volumes of fluids on a daily basis under physiological condition (Kenney and Chiu 2001). Many elderly people cannot maintain body water homeostasis with the progression of aging (Luckey and Parsa 2003). Aging is a natural process, which is followed by a progressive decrease or disturbance in the water metabolic balance (Stout et al. 1999). As described by many laboratories (Hooper et al. 2014), in the progress of aging, the proportion of human body fluid compared to body weight reduces from over 70% in newborn babies to 60% in childhood and about 50% in older people (Altman and Katz 1961; Friis-Hansen et al. 1951; Greenleaf 1998; Olde Rikkert et al. 1997). As shown in Fig. 5.1, Li et al. demonstrated a decrease in both the frequency and quantity of water intake of ten-month-old mice (C57BL/6j wild-type) compared with those of one-month-old ones (Li et al. 2012). Bethancourt et al. (2020) showed that hydration status and water intake were moderately associated with attention/processing speed among females. This natural reduction is suspected and considered to be the cause of reduced hydration in normal individuals under non-pathological conditions.

Fig. 5.1

A decrease in frequency and quantity of drinking water as aging. The drinking frequency per hour of mice (C57 BL/6) was monitored with an infrared CCD camera (panel a). The drinking frequency (counts per hour) of ten-month-old mice was significantly lower than one-month-old as control (*P panel b). The drinking quantity in 72 h for ten-month-old mice was much less than that for one-month-old as control (**P < 0.01). Data were reprinted with permission from Acta Neuropharmacologica (Li et al. 2012)

3 Diminished Thirst Sensation as Aging

The regulation of thirst is a complex process involving multiple pathways. Fluid intake is an essential innate behavior mainly caused by the two osmotic and hypovolemic types of thirst (Pool et al. 2020). During dehydration, rehydration, and reestablished euhydration, conscious perception responses to subconscious regulatory dynamic interactions were investigated (Armstrong et al. 2020). Cerebral circumventricular organs in the lamina terminalis are believed to be critical sites for sensing osmotic and hypovolemic types of thirst-inducing stimuli. As described by Matsuda et al. (2017), neurons projecting to the organum vasculosum lamina terminalis control water intake, while those projecting to the ventral part of the bed nucleus of the stria terminalis control salt intake. Using single-cell sequencing of water-deprived Drosophila, Park et al. (2022) identified molecular and cellular adaptations in the fly brain. They revealed that thirst elevates astrocytic D-serine release, binding to neural NMDA-type receptors, and awakens quiescent glutamatergic circuits to enhance water consumption. Elucidating that thirst is a multimodal physiological state by using single-cell RNA-seq, Pool et al. (2020) demonstrated that in the mammalian brain, different thirst states are mediated by specific neurons. The mechanisms regulating osmotic and hypovolemic types of thirst may underlie the selective intakes of water and/or salt in the subfornical organ, which may contribute to human fluid homeostasis (Matsuda et al. 2017).

Because of its importance to life, the sensation (thirst) to water develops in the early stage. The process that leads to thirst due to renin or intracellular dehydration before weaning is complete (Leshem and Epstein 1988). Aging is associated with a decrease in thirst sensation, which makes old people more susceptible to dehydration (Quirós Cognuck et al. 2022). Dehydration is primarily attributable to inadequate water intake, which could be caused by the dysfunction of the central nervous system mechanisms controlling thirst. The phenomenon of reduced thirst in response to dehydration in aging was first observed decades ago and has been examined extensively since then. The reduced thirst and ingestive behavior have been reported consistently in response to hyperosmotic stimuli, hypovolemic stimuli, and dehydration in both elderly humans and animal models of aging (Begg 2017).

Elderly people (over the age of 65 years) fail to perceive thirst, and thus they face the risk of dehydration. It is a fact that the elderly progressively diminish thirst sensation, followed by decreasing fluid intake as they age (Kenney and Chiu 2001). Especially in a challenging situation, for instance, exercising in a warm environment, a hyperosmotic stimulus, or fluid deprivation, elderly adults could exhibit diminished thirst sensation and reduced fluid intake, compared with young adults. According to an investigation in Germany, very old elderly but not the independently living elderly require special attention with respect to adequate supply of fluid (Volkert et al. 2005). During the long process, aging alters all physiological control systems, including the regulation system associated with thirst and satiety. For the elderly, full fluid restoration eventually occurs though full restoration of fluid balance (Kenney and Chiu 2001).

In the elderly population, depression is regarded as the most common pathological cause for loss of body weight. The reduction in the feeling of thirst and water intake gradually causes chronic dehydration. On the one hand, diminished responses to sodium may be another reason to decrease the intake of water. As described by Begg (2017), the reduced thirst and ingestive behaviors respond to hyperosmotic stimuli, hypovolemic stimuli, and dehydration in both elderly humans and animal models of aging. On the other hand, decreased water intake could result from physiological anorexia (Morley 2002). In fact, anorexia among elderly individuals again is caused by multiple reasons and alterations, such as increased leptin levels, fundal compliance, and hedonic qualities of food. So far, the precise etiology and mechanism of reduced thirst remain to be investigated, although there has been evidence to suggest that aging disturbs the physiological response to and regulation of body fluid and sodium homeostasis.

4 Dehydration and Age-Related Cognitive Impairment

4.1 Dehydration as a Predictor of Cognitive Status

Chronic dehydration is one of the risk factors involved in age-related cognitive impairment. According to Gharibzadeh and Hoseini (2007), weight loss primarily results from chronic dehydration, which may be one of the preventable risk factors for Alzheimer’s disease (AD). The slow, progressive weight loss associated with aging may speed up prior to the onset of age-related dementia, according to Purdy (Purdy 2006). Archer et al. have examined the differences, interactions, and associations among cognition, fluid intake, and demographic variables for psychogeriatric inpatients aged 65 years or older. As shown in their results, elderly adults with and without cognitive impairment had different fluid intake over time. They emphasized that the fluid intake of elderly patients with or without cognitive impairment must be monitored throughout their hospitalization (Archer et al. 2015).

Dehydration can also be used as a reliable predictor of impaired cognitive status besides other complications (Warren et al. 1994; Miller et al. 1998). According to Wilson and Morley, dehydration frequently results in delirium as a manifestation of cognitive dysfunction. The cognitive impairment could not be completely reversible, even though the occurrence of delirium appears to be transient acute global cerebral dysfunction (Wilson and Morley 2003). The activity of nitric oxide synthase (NOS) is reduced in the cortex and striatum of rats with aging (Calka et al. 1994). The decrease of activity of NOS occurring with aging may blunt the increase in NOS in dehydration and possibly interfere with memory processing and cognitive function (Salemme et al. 1996). However, the cause of cognitive impairment that resulted from dehydration is definitely complex. As described by Koch and Fulop (2017), various hormonal and kidney changes occur, both affecting water homeostasis with aging. Aging is a risk factor for chronic kidney disease (CKD), and many features of CKD are reproduced in the aging kidney. Imbalance of ions also affects our brain and cognitive ability during dehydration. We should consider more effects resulted from different factors. When using dehydration to predict cognitive status, we must also consider the influence of other factors.

4.2 Dehydration and Alzheimer’s Disease

In 1989, Albert et al. found that elderly individuals with AD are at increased risk of dehydration during periods of fluid restriction due to loss of normal physiological responses of thirst (Albert et al. 1989). Mueller and Boisen (1989) paid attention to dehydration and claimed: “Keeping your patient’s water level up.” In fact, weight loss can be observed in elderly patients in clinics, which is a major clinical feature of AD (Koopmans et al. 1992). Significant weight loss in a short period is often related to increased disease severity and even mortality (Luckey and Parsa 2003; Gillette et al. 2007). Consequently, chronic dehydration has been regarded as a common symptom of patients with age-related cognitive impairment, particularly those with AD (Buffa et al. 2010).

Amyloid β deposition and Tau hyperphosphorylation in paired helical filaments are two of the most typical pathological features. Dehydration and hyperosmotic stress trigger Tau phosphorylation in human neuroblastoma cells and induce apoptosis (Tanii et al. 2000; Stoothoff and Johnson 2001; Saikia et al. 2014; Nguyen et al. 2020). According to Buffa et al., malnutrition typically develops during the mild to moderate stages and tends to worsen to dehydration in the severe stage in Alzheimer’s patients (Buffa et al. 2010). Therefore, it needs to explore the relationship between age-related cognitive impairment and dehydration needs to be explored, especially chronic dehydration. As shown by Nishi et al. (2023), decreases in global cognitive function were associated with reduced physiological hydration status over a two-year period in older adults with obesity and metabolic syndrome. They believe further work should focus on the effect of hydration on cognitive performance over a longer duration.

5 Formaldehyde and Age-Related Cognitive Impairment

5.1 Dysmetabolism of Formaldehyde Is Related to Aβ Deposition and Tau Hyperphosphorylation

Recently, formaldehyde is a major risk factor involved in the progression of age-related cognitive impairment (Su et al. 2016). Formaldehyde at low concentrations induced Tau protein aggregation (Nie et al. 2007a), which was implicated in cytotoxicity and neural cell apoptosis (Nie et al. 2007b; Chi et al. 2012). Oral administration of methanol (the metabolic precursor of formaldehyde) promoted the formation of senile plaques (SPs) and tau hyperphosphorylation in the brains of monkeys, accompanied with a decline in working memory (Yang et al. 2014a, b). Furthermore, intravenous injection of formaldehyde through the tail vein activated glycogen synthase kinase-3β (GSK-3β) and tau hyperphosphorylation in the brain of C57BL/6j wild-type mouse (Lu et al. 2013; He et al. 2016).

Emotional behaviors of animals, including depression and anxiety, were affected by formaldehyde steam (Leitl et al. 2014; Li et al. 2016a). Although the effect of formaldehyde on brain dysfunction has been widely studied (Mei et al. 2015; Su et al. 2016), the relation of formaldehyde with dehydration and age-related cognitive impairment needs to be deeply investigated.

5.2 Dehydration Leading to High Levels of Formaldehyde

To investigate whether dehydration is involved in formaldehyde metabolism or not, Li et al. employed C57BL/6j mice which were deprived of water to induce hypovolemic dehydration. As shown in Fig. 5.2, the concentration of brain formaldehyde in mice significantly increased in 72 h in water deprivation (Li et al. 2012). Consequently, Li et al. established a mouse model to simulate chronic dehydration. They administrated C57 BL/6j mice with 4% NaCl instead of water intake for three months to induce hypertonic dehydration. In the 4% NaCl-fed group, the mice showed symptoms of chronic dehydration in which their serum osmotic pressure and sodium concentration significantly increased, accompanied with a decrease in body weight (Li et al. 2016b). The levels of formaldehyde were markedly elevated in the brain of the 4% NaCl-fed mice. As shown by these data, both acute (hypovolemic) dehydration and chronic (hypertonic) dehydration can induce dysmetabolism and elevated levels of brain formaldehyde.

Fig. 5.2

An increase of mouse brain formaldehyde in the limit of drinking water. Two-month-old C57 BL/6 mice were deprived of drinking water for 72 h and the concentration of their brain formaldehyde was measured with DNPH coupled with HPLC as described. The age-matched C57 BL/6 mice were employed as control. The concentration of brain formaldehyde of the water-deprived mice is significantly higher than that of control (*P = 0.037, n = 8). This figure was reprinted with permission from Acta Neuropharmacologica (Li et al. 2012)

5.3 Levels of Formaldehyde Increase with Aging

As mentioned above, dehydration either physiologically or pathologically occurs in the elderly population (over the age of 65 years) with aging. Similarly, according to Tong et al., a progressive increase in the levels of endogenous formaldehyde could be observed in elderly individuals (over the age of 75 years) in epidemiological investigation (Tong, et al. 2013). They found that the concentration of hippocampal formaldehyde in rats gets higher with age. The concentration of brain formaldehyde in ten-month-old mice was higher than that in three-month-old ones (Li et al. 2016c). The formaldehyde content in the brain of senescence-prone strain 8 (SAMP8) mice was significantly higher than that of senescence-resistant strain 1 (SAMR1) as a control group (Qiang et al. 2014). Very recently, Liu et al. revealed that the transgenic APP/PS1 mouse (a typical AD animal model) suffers from abnormally high levels of formaldehyde from the intestinal microbiota (Liu et al. 2017). All these data suggest that the metabolic rate of endogenous formaldehyde is dependent on human age.

5.4 Patients with Cognitive Impairment Suffer from Formaldehyde Dysmetabolism

Formaldehyde is produced and processed in all human cells including neural cells; thus, dysmetabolism of formaldehyde is involved in multiple pathways. However, the most sensitive organ or cell prone to dysmetabolism of formaldehyde remains unknown. According to our investigation, we would like to conclude that the brain is the most sensitive. The concentrations of urine formaldehyde are positively related to the decline of cognitive ability, not only in AD inpatients but also in elderly individuals living in the communities in Beijing (Tong et al. 2011). As shown in Chap. 9, even education levels are closely correlated with the levels of urine formaldehyde in the elderly individuals in Beijing communities (Yu et al. 2014). In fact, formaldehyde is associated with dementia in patients with either AD or VD (vascular dementia) (Qiang et al. 2014; Chen et al. 2014; Tong et al. 2017). However, endogenous formaldehyde cannot be used as a reliable biomarker to differentiate between AD and VD. As a non-invasive biomarker, endogenous formaldehyde can be used for age-related cognitive impairment in the preclinical stage, clinical stage, and epidemiological investigation for AD.

5.5 Increasing Formaldehyde Concentration Decreases Water Intake

As mentioned above, both the frequency and quantity of water intake progressively decrease with aging, followed by an increase of brain formaldehyde. Brain formaldehyde in ten-month-old mice was significantly higher than that in young ones (Li et al. 2012). These data alone could not clarify whether formaldehyde interferes with drinking behaviors. In order to clarify whether formaldehyde can affect water intake, Li et al. administrated C57BL/6j mice with formaldehyde (0.5 mg/kg, once daily) through intraperitoneal injection. As their result shows, the frequency and quantity of water intake markedly decreased a week after the mice were injected with formaldehyde (Li et al. 2016b).

5.6 Vicious Circle of Dehydration, Formaldehyde, and Cognitive Impairment

The interaction between dehydration and cognitive impairment could create a vicious cycle. On the one hand, we know that dehydration affects SSAO and formaldehyde dehydrogenase 3 (ADH3), as well as ALDH2, leading to an imbalance in the metabolism of the aldehyde between the two enzymes and the elevation of brain formaldehyde (Li et al. 2016b). Water deprivation in 72 h enhances the production of endogenous formaldehyde, especially in the brain (Li et al. 2012). On the other hand, injection with formaldehyde decreases the frequency and volume of water intake (Li et al. 2016b). Elevation of serum arginine vasopressin (AVP) levels could be detected when there is a distinct increase in the brain formaldehyde level after the injection. The concentration of serum angiotensin II (ANG II) significantly increased after the administration of formaldehyde. A significant increase in serum aldosterone (ALD) was detected as a result of the increased angiotensin levels. These data indicate that formaldehyde promoted AVP and ALD expression by increasing the level of serum ANG II.

As shown in Fig. 5.3, chronic dehydration associated with formaldehyde dysmetabolism may be a preventable risk factor for Alzheimer’s disease (Gharibzadeh and Hoseini 2007) (Chap. 18). Aging may diminish the sensation of thirst (Kenney and Chiu 2001), leading to decreased water intake and chronic dehydration (Begg 2017). Chronic dehydration can result in the imbalance of formaldehyde metabolism, which also affects cognitive ability, including forgetting to drink water (Li et al. 2012, 2016b). Formaldehyde dysmetabolism has been observed in ~35% of patients with age-related cognitive impairment (Wang et al. 2017). Cognitive impairment further worsens the diminished thirst sensation (Constans 2005).

Fig. 5.3

Diagram for a putative “vicious circle” of dehydration, formaldehyde, and cognitive impairment

6 Changes in Catecholamine and Behaviors

According to Liu et al. (2009), rats treated with inhalation formaldehyde (monitored to be 13.5+/−1.5 ppm) showed more aggressive behavior. At the same time, they observed a significant elevation in dopamine (DA) and a significant decrease in 5-hydroxltryptamine (5-HT) in the frontal cortex synaptosome. To study whether or not dehydration disturbs the anabolism and metabolism of catecholamine, Li et al. (2016b) employed the chronic dehydrated mouse model (C57 BL/6j mice fed with 4% NaCl instead of water intake for 3 months). With a high level of formaldehyde, the chronically dehydrated (4% NaCl-fed) mice have their brain 5-HT markedly decreased, acting as slow learners in the “shuttle box” behavior assay compared with those fed with water as control (Li et al. 2016b). Sequentially, they intraperitoneally injected a C57BL/6j mouse with formaldehyde for a week and also detected a lower level of 5-HT and slow learning in the animal in the shuttle box (Fig. 5.4). As a control, a 4% NaCl injection did not result in any significant differences in 5-HT levels and behavior assays. Their data indicated that chronic dehydration leads to dysregulation of brain formaldehyde, accompanied with a marked decrease in 5-HT levels in the mouse brain and a decline in learning in the shuttle box.

Fig. 5.4

Level changes of 5-HT, Ach, and DA in the mouse brain. The levels of 5- hydroxltryptamine (5-HT, a), acetylcholine (Ach, b), and dopamine (DA, c) in the brain of 4% NaCl-treated mice were detected by ELISA kits for the three-month group. Meanwhile, the 5-HT concentration of mice injected intraperitoneally with formaldehyde or 4% NaCl was also detected (d). The data are shown as the mean SE; *P < 0.05; **P < 0.01. (Li et al. 2016b)

As described by Kjaer et al. (1994), dehydration induces vasopressin release. To study why the serotonin level decreases in dehydration, Li et al. (2016b) observed changes in AVP levels during dehydration. Levels of both SSAO and AVP markedly increase in the serum of NaCl-induced mice. Then, they injected normal C57 BL/6j mice with AVP and detected distinctly increased SSAO levels of enzymic activity and protein expression (Li et al. 2016b). As shown in Fig. 5.5, SSAO catalyzes primary amines producing formaldehyde by deamination. At the same time, serotonin is broken down to 5-hydroxyindole acetaldehyde, also catalyzed by SSAO, followed by formation of 5-hydroxyindoleacetic acid as shown in the literature (Fitzgerald et al. 1990; O’Sullivan et al. 2003; Höglund et al. 2019; Lin et al. 2020). It is probable that the decrease in serotonin is associated with the change in SSAO activity in dehydration.

Fig. 5.5

A putative diagram for water deprivation and serotonin decrease. The putative scheme is referred to authors’ work (Li et al. 2016b, c)

Dopamine is one of the catecholamine neurotransmitters playing an important role in the control of motor activity and emotional behavior. Tyrosine hydroxylase (TH) is a rate-limiting enzyme for DA synthesis. After the mice had been exposed to 2 ppm formaldehyde for one week, their immobility time increased significantly in the forced swimming test, indicative of depression-like behavior. Noticeably, the number of TH-immunoreactive neurons decreased significantly under the same conditions (Li et al. 2016a). More research on the relationship between depression behaviors and formaldehyde should be carried out to clarify the pathomechanisms that underlie. Mei et al. observed that norepinephrine deficiency induced by formaldehyde played a role in age-related memory loss (Mei et al. 2015). Except for “shuttle box” learning deficiency, long-term 4% NaCl-fed mice did not show significant differences in other behavioral tests such as Y maze, radial arm maze, elevated plus maze, and the open field test. No noticeable results were observed in grooming and the time spent in the central square in the open field test (Li et al. 2016b). All these results suggest a low possibility that long-term 4% NaCl-fed (hypertonic dehydrated) mice suffer from anxiety-like moods. However, rats with water deprivation also showed a decrease in 5-HT with marked anxiety mood (Chatoui et al. 2020). Dehydrated rats exhibited more preference for the dark compartment, suggesting that prolonged water deprivation is associated with an anxiogenic effect. Different testing models, such as the 4% NaCl-fed model and water deprivation, may produce different results in anxiety behaviors. For 4% NaCl-fed (hypertonic dehydrated) mice, it appears that the “shuttle box” learning paradigm processes “a punishment with electric shock,” which makes mice painful and fearful. 5-HT plays a role in animal behaviors of fear, according to Bocchio et al. (2016). In addition, the relationship between 5-HT and emotional learning in mice with hypovolemic dehydration needs further investigation.

7 Dynamic Daily Changes in Levels of Formaldehyde

To follow the changes in the concentrations of endogenous formaldehyde daily, Li et al. recruited 20 young participants (9 male, 11 female, 25–35 years old) to take part in the “Investigation of the relation between urine formaldehyde and water intake.” The participants’ demographic characteristics and daily actions were described (Li et al. 2016c). The levels of endogenous formaldehyde reach the highest in the morning before breakfast, remarkably decrease around noon, and then increase again at night. The concentration of urine formaldehyde at noon was noticeably elevated while the participants were not allowed to drink water or any other beverages (water intake deprivation) from 8:30 to 12:30 (Li et al. 2016c). Furthermore, Li et al. gave the participants “fried chicken” without water deprivation for three meals daily. After two days, an increase in endogenous formaldehyde was observed in the participants (Li’s unpublished data). These data indicate that water intake is essential for individuals to eliminate endogenous formaldehyde due to the soluble characteristic of the aldehyde.

8 Water Intake Is Beneficial to Eliminate Endogenous Formaldehyde

We would like to emphasize that “water intake in the morning” is more effective because of the high levels of formaldehyde occurring at that time of the day (Li et al. 2012). “Water intake at night” is also recommended, but someone should have to get up to urinate at night, which may interfere with sleep. Protection of our brain should be carried out at an early stage when neural cells are living actively. For example, crops undergoing a brief drought can recover after irrigation. However, those crops will die of a long-term drought even though you water them fully. Albert et al. found a positive correlation between the quantity of water intake and the MMSE score (Albert et al. 1994). A 21-year investigation performed by Eskelinen et al. showed that drinking tea or coffee can decrease the risk of onset of age-related cognitive impairment (Eskelinen et al. 2009). In this laboratory, we observe the protective effects of resveratrol on neural cells in the presence of formaldehyde (Miao et al. 2013; He et al. 2016). Thus, we would like to recommend tea, coffee, or some other beverages containing resveratrol. They should be beneficial in clearing excess formaldehyde from our body. Hooper et al. also proposed strategies to increase fluid intake in residential care homes (Hooper et al. 2014). They found that elderly individuals suffer from physical inability to reach drinks, reduce social drinking, and diminish drinking pleasure. Polito et al. emphasized the anti-amyloid-beta effects of tea, and drinking tea is regarded as a natural complementary therapy for neurodegeneration (Polito et al. 2018; Afzal et al. 2022). Therefore, recognizing and overcoming the barriers impeding water intake among the elderly should be paid attention to (Hooper et al. 2014). According to the guidelines released by the China Nutrition Association (CNA) (Chen et al. 2013), water intake for male and female adults is 1.7 L and 1.5 L daily, respectively, in addition to water contained in food. As mentioned above, levels of endogenous formaldehyde in the human body are highest in the morning. It is recommended that healthy adults should drink 400–500 ml of water (male) and 350–400 ml of water (female) after getting up and before breakfast (Li et al. 2012). Water could be warm boiled water, or mineral water. Tea, coffee, or some other beverage, as one likes, can be used (Panza et al. 2015; Beck et al. 2021). According to Eskelinen et al. (2009), coffee drinking at midlife is associated with a decreased risk of dementia/AD later in life. Green tea polyphenols, especially epigallocatechin gallate, were found to have anti-Alzheimer and anti-aging properties, possibly preventing system-level structural damage (Afzal et al. 2015). Formaldehyde is easy to dissolve in water. Water aids in the elimination of excess formaldehyde through kidneys. Individuals can consume the remaining water (1000–1200 ml daily) divided in the morning, at noon, in the afternoon, and in the evening, according to one’s own habits (Li et al. 2016b). Tea is also strongly recommended to mitigate the harm from excess formaldehyde because of its protective effect on cognitive ability (Jiang et al. 2023; Li et al. 2023; Sirui et al. 2023). Water intake eliminates not only excess formaldehyde but also other harmful metabolic products.

9 Conclusion

Chronic dehydration may be caused by reduced thirst and/or memory loss. Chronic dehydration diminishes the elderly’s ability to eliminate metabolic products, leading to the accumulation of cytotoxic compounds, including formaldehyde. Dehydration and formaldehyde accumulation interfere not only with water intake behavior but also with cognitive ability. Age-related cognitive impairment diminishes the sensation of thirst and worsens dehydration, leading to formaldehyde accumulation. Consequently, the accumulated formaldehyde in the brain could impair cognitive ability, for instance, making the individual forget to drink water and worsening the chronic dehydration. That creates and experiences a vicious cycle as an elderly age. The highest concentration of endogenous formaldehyde is found in the morning, followed by a decrease around noon, and an increase in the evening. Thus, regular water intake, including tea (Li et al. 2022), is recommended to intervene and reduce the accumulation of formaldehyde and other side-metabolic products, especially when it is taken in the morning.

10 Prospective

Regularly drinking green tea as an antioxidant benefits physical and mental health, delaying brain and skin aging (Sivamaruthi et al. 2024). To eliminate and decrease endogenous formaldehyde, we would like to recommend drinking tea daily because tea contains tea polyphenols, for instance, epigallocatechin gallate (EGCG), which suppresses β-amyloid-induced neurotoxicity by inhibiting GSK3β activation and other adverse molecular pathways (Lin et al. 2022). Tea can be used as a food source of inhibitors on acetylcholinesterase regardless of brewing conditions (Baranowska-Wójcik et al. 2020). Oxidative stress and mood problems are believed to be dementia risk factors, but tea polyphenols may regulate and maintain emotional homeostasis (Minné et al. 2023). As shown by an epidemiological investigation, tea consumption probably decreases the risk of cognitive impairment to some extent in the elderly population (Li et al. 2022). Therefore, keeping a good habit of drinking tea daily is good for our health, as it contributes to the elimination of endogenous formaldehyde, formic acid, and other metabolic products.

Acknowledgments

This project was supported by the Joint Project of Inner Mongolia Medical University (YKD2021LH074), Central Leading Local Science and Technology Development Fund Project (2020SZY0464). Besides, the grants supporting this project are exhibited in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_6

6. The Role of Formaldehyde in Cell Proliferation and Death

Weichuan Mo¹ and Rongqiao He1  

(1)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Accumulating public attentions have been paid to the neurotoxicity of formaldehyde during aging and carcinogenesis induced by environmental and occupational formaldehyde exposure. The cytotoxicity and carcinogenesis by formaldehyde manifestly reveal two distinct cellular functions of formaldehyde: inducing cell death and promoting cell proliferation. The degree of the disturbance of the formaldehyde baseline determines the effect of formaldehyde on cells. This chapter classifies the dose ranges of formaldehyde based on its role in cell proliferation and death and discusses the mechanisms underlying the nonlinear dose- and time-dependent effects of formaldehyde, which would give light to our knowledge on the physiological and pathological effects of formaldehyde. Short-term small interruption on the formaldehyde baseline, that is, formaldehyde elimination by formaldehyde capturers and addition of low concentration of formaldehyde (<0.1 mM), provides a pro-proliferative environment for cancer cell lines by activating extracellular-regulated protein kinase (ERK) pathways and raising genomic instability, which contributes to the carcinogenesis of formaldehyde. Moderate concentration of formaldehyde (0.1–1 mM) further increases the formaldehyde-induced DNA damage (DNA adducts and DNA–protein cross-links), which overwhelms the cellular DNA repair capacity and triggers programmed cell death, especially apoptosis. In addition, moderate concentration of formaldehyde induces oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, proteotoxicity, and excitotoxicity delivered by prolonged Ca²⁺ releasing in neurons, which subsequently lead to apoptosis. Moderate concentration of formaldehyde plays a role in autophagy and cell senescence, as well. High concentration of formaldehyde (>1 mM) induces necrosis. Particularly, neuronal cells are more sensitive to the toxicity of formaldehyde. The necrosis-inducing dose of formaldehyde also depends on cell density.

Keywords

FormaldehydeCarcinogenesisNeurotoxicityApoptosisCell proliferationDNA adductsDNA–protein cross-link

Abbreviation

AD

Alzheimer’s disease

ADH5

Aldehyde dehydrogenase 5

BDNF

Brain-derived neurotropic factor

CNS

Central nervous system

DPX

DNA-protein cross-links

ER

Endoplasmic reticulum

ERK

Extracellular-regulated protein kinase

FA

Formaldehyde

H₂S

Hydrogen sulfide

IARC

International Agency for Research on Cancer

iHCECs

Immortalized human corneal epithelial cells

iHConjECs

Immortalized human conjunctival epithelial cells

iHMGECs

Immortalized human meibomian gland epithelial cells

MDA

Malondialdehyde

Res

Resveratrol

ROS

Reactive oxygen species

VE

Vitamin E

1 Introduction

High dose of formaldehyde is definitely lethal to living cells. Direct contact with formalin solution causes inflammatory alterations in the skin. Inhalation of formaldehyde gas in the air is irritating to the mucous membranes of the respiratory tract and induces cognitive deficits (Li et al. 2020a; Li et al. 2020b). Necrosis and apoptosis were observed in cells treated with formaldehyde at high concentrations. Neuronal cells were more sensitive to formaldehyde. Aging-related endogenous formaldehyde accumulation leads to apoptosis in neuronal cells and subsequently results in brain and cognitive damages (Mei et al. 2015; Cui et al., 2016; Ai et al. 2019; Yi et al. 2020; Li et al. 2021). The cytotoxicity of formaldehyde is closely related to DNA damage, oxidative stress, mitochondrial dysfunction, and proteotoxicity.

Meanwhile, accumulating evidence has shown that formaldehyde exposure raises carcinogenic risk (Swenberg et al. 2013; Kang et al. 2021; Protano et al. 2021; Cammalleri et al. 2022; Khoshakhlagh et al. 2018). The International Agency for Research on Cancer (IARC) classified formaldehyde as a Group 1 human carcinogen (IARC 2012). The evidence that formaldehyde is a carcinogen is strong for nasopharyngeal cancer, as the nasopharyngeal airway is the initial target site for formaldehyde and persistent formaldehyde-caused DNA damage is considered involved in the formaldehyde-related nasopharyngeal cancer (McGregor et al. 2006; Bono et al. 2016). The threat of widespread low-level formaldehyde exposure and the occupational contact to the environmental formaldehyde have raised public health concerns (Binazzi et al. 2015; Protano et al. 2021; Cammalleri et al. 2022). The pro-proliferative effect of low-dose formaldehyde exposure is believed to cause carcinogenesis, which is attributed to the genotoxicity and mutagenesis by formaldehyde.

The cytotoxicity and carcinogenesis by formaldehyde manifestly reveal two distinct cellular functions of formaldehyde: inducing cell death and promoting cell proliferation. Since cellular activities were conducted under the context of endogenous formaldehyde, the degrees of the disturbance of the endogenous formaldehyde baseline determine the action of formaldehyde on cells. This chapter discusses the dose ranges of formaldehyde based on its role in cell proliferation and death and tries to clarify the mechanisms underlying the nonlinear dose- and time-dependent effects of formaldehyde, which may give light to our knowledge on the physiological and pathological effects of formaldehyde.

2 The Formaldehyde Baseline

The endogenous formaldehyde concentration serves as the formaldehyde baseline. Balancing the rapidly metabolic processes of formaldehyde and detoxification pathways of exogenous formaldehyde input (see Chap. 2 for details) results in a physiological formaldehyde level at approximately 10–80 μM in the serum, urine, and cerebrospinal fluid of healthy individuals (He et al. 2010; Tong et al. 2011, 2013a; Dorokhov et al. 2018; Chen et al. 2019; Xin et al. 2019; Li et al. 2021).

For cell cultures, the formaldehyde baseline is the background concentration of formaldehyde in the medium. The residual formaldehyde level in the serum-free medium was ~5 μM (Chen et al. 2014; Sun et al. 2013). Formaldehyde probing showed that the added formaldehyde in the medium crosses the cell membrane immediately and alters the intracellular formaldehyde level (Brewer and Chang 2015; Xu et al. 2016; Sheng et al. 2021). Therefore, the endogenous formaldehyde level in cell cultures directly reflects the formaldehyde concentration in the medium under the experimental condition. Recently, Sheng et al. developed a novel fluorescent probe Mem-FA which can sensitively detect and distinguish the internal and external sources of formaldehyde on the cell membrane and thus is capable of specifically tracing the dynamic changes in cellular formaldehyde level and distribution (Sheng et al. 2021). With the development of subcellular organelle targeted formaldehyde probes, the intracellular formaldehyde localization has been visualized and dynamically recorded in the ER, Golgi apparatus, lysosome, and mitochondria (Chen et al. 2017; Tang et al. 2016; Chen et al. 2019; Xin et al. 2019; Fortibui et al. 2021; Liu et al. 2022), indicating that formaldehyde is a by-product of many metabolic biochemical reactions and concentrated in organelles involved in the synthesis, modification, and degradation of biomacromolecules but toxic to energy metabolism.

3 Pro-proliferative Small Interruption on Formaldehyde Baseline

Small elevation of formaldehyde concentration in the cell culture medium (10 nM–100 μM) above the formaldehyde baseline (~5 μM) enhances cell proliferation, showing a Hormesis effect (Agathokleous and Calabrese 2021), and the pro-proliferative dosage is cell-type dependent. The proliferation of HeLa cell and human malignant melanoma SK-MEL-28 cell is stimulated with the addition of 10 μM formaldehyde (Ke et al. 2014; Rizzi et al. 2016). Formaldehyde (10–25 μM) enhances the proliferation of both human low-invasive A375P (1-day exposure) and high-invasive SK-MEL-28 cells (3-day exposure) (Rizzi et al. 2014, 2016). 50 μM formaldehyde accelerates the proliferation of human neuroblastoma SH-SY5Y cell (Li et al., unpublished data). A total of 100 μM formaldehyde stimulates the proliferation and reduces apoptosis in human colon carcinoma HT-29 cell and human endothelial HUV-EC-C cell (Tyihak et al. 2001). Formaldehyde at 75 and 40 μM significantly promoted the proliferation of human chronic myeloid leukemia cells (K562 cells) and human bronchial epithelial cells (16HBE cells), respectively (An et al. 2019). The addition of formaldehyde at 10 nM–10 μM increased the proliferation of human choriocarcinoma cell (JEG-3) (Lee et al. 2017).

Meanwhile, a formaldehyde shortage situation is also beneficial for cell proliferation. Szende et al. have shown that resveratrol (Res), a formaldehyde capturer, increases the proliferation of many cancer cell lines at low concentration (0.1–1.0 μg/mL) and proposed that Res facilitates the elimination of formaldehyde in the medium by directly reacting with formaldehyde (Szende et al. 2000). Noteworthy, their results also suggested that, when Res was at high concentration, the reaction production of Res and formaldehyde would induce apoptosis, instead. Wu et al. showed that aldehyde dehydrogenase 5 (ADH5), a formaldehyde degradation enzyme, is a repressor of neural differentiation. The expression of ADH5 decreases during neurogenesis. The overexpression of ADH5 counteracts the differentiation of human neural stem cells, suggesting that proliferative neural stem cells prefer a low formaldehyde environment, and that the neural maturation progresses are more likely to occur under a high formaldehyde condition (Wu et al. 2014).

In addition, the pro-proliferative effect of low-concentration formaldehyde is largely a short-term effect. Long-term low-dose formaldehyde could also induce apoptosis. Our laboratory confirmed that, instead of the short-term pro-proliferative effect, long-term exposure to formaldehyde at a low concentration (15 μM) gradually induced damage in cell morphology and eventually led to cell death in murine neuroblastoma N2a cell line and primary hippocampal neurons (Wang et al. 2017). Chen et al. showed that 5 days exposure of 33–83 μM formaldehyde significantly decreased the viability of immortalized human meibomian gland epithelial cells (iHMGECs), immortalized human corneal (iHCECs), and conjunctival (iHConjECs) epithelial cells which could be protected by the supplementation with epidermal growth factor and bovine pituitary extract (Chen et al. 2018). Even a 9-day formaldehyde exposure at the concentrations from 1 pM to 10 nM induced apoptosis in human colorectal cancer SW620 cells (Lee et al. 2016), which further confirmed the cytotoxicity of a long-term low-concentration formaldehyde exposure.

3.1 Mutagenesis and Genotoxicity

The pro-proliferative effect of formaldehyde is believed to cause carcinogenesis, which is mainly attributed to the mutagenesis and genotoxicity by formaldehyde (Thompson et al. 2020). Formaldehyde directly targets various nucleophiles of DNA, proteins, and amino acids, which induce DNA damages and epigenetic changes by forming adducts with DNA and proteins. Careful physical chemistry-based mode of action studies illustrated that formaldehyde mainly induces two types of DNA damages: DNA adducts and DNA–protein cross-links (DPX).

The interaction of formaldehyde to DNA occurs on the amino groups of base pairs, which is pro-mutagenic (Swenberg et al. 2011). Point mutations in p53 tumor suppressor gene were identified from formaldehyde-induced (>10 ppm) squamous cell carcinomas in the nasal tissues of rats (Recio et al. 1992; Wolf et al. 1995). DPX are genotoxic as a result of their ability to arrest DNA replication (Szende and Tyihak 2010). The accumulation of formaldehyde-induced DNA adducts and DPX induces the regenerative proliferative response of nasal epithelial cells (Hester et al. 2003). The response is believed to be necessary to replace the damaged epithelium and to protect the nasal airway from further irritation by formaldehyde, which is closely associated with subsequent nasal cancer development (Monticello et al. 1996; Swenberg et al. 2013). The genetic instability, caused by the overload of formaldehyde-induced DNA damages and/or interruptions with the DNA repair signaling pathway, is essential for carcinogenesis (Zhang et al. 2010a). Non-cytotoxic (<100 μM) formaldehyde concentrations may exert an adjuvant role in carcinogenesis by impeding the excision of multiple mutagenic base lesions (Luch et al. 2014). DNA adducts and DPX activate DNA repair pathways. By using CRISPR-based functional genomics screening, Zhao et al. confirmed that ADH5 and FANC family genes play major roles in formaldehyde metabolism and Fanconi anemia pathway in formaldehyde tolerance (Zhao et al., 2021). Knockout of ADH5 accumulates endogenous formaldehyde and results in the increase of DNA adducts in mice. FANCD2, a DNA cross-link repair protein, is involved in the repair of this kind of damage. Double knockout of ADH5 and FANCD2 in Chicken DT40 cell lines led to hypersensitive to formaldehyde, presenting DNA damage and genome instability (García-Calderón et al. 2018). ADH5 (−/−) FANCD2 (−/−) mice showed bone marrow failure eventually developed leukemia and fatal malignancies (Pontel et al. 2015). Dingler et al. found that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia and that analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome (Dingler et al., 2020). By using disease model cell lines, including induced pluripotent stem cells, Mu et al. demonstrated that ADH5 is the primary defense against formaldehyde, and ALDH2 provides a backup. DNA repair capacity in the ADH5/ALDH2-deficient cell lines can be overwhelmed by exogenous low-dose formaldehyde, as indicated by higher levels of DNA damage than in FANCD2-deficient cells. ADH5/ALDH2-deficient disease model induced pluripotent stem cells displayed increased levels of DNA damage as well as defective cell expansion when stimulated into hematopoietic differentiation in vitro (Mu et al. 2021).

3.2 DNA-Damage-Independent Pro-proliferative Effect of Formaldehyde

Low-concentration formaldehyde also induces cell proliferation in a DNA-damage-independent way. Aizenshtadt et al. stimulated the proliferation of human epidermoid carcinoma A431 cells by exposing the cells to 30 μM formaldehyde for 5 min (Aizenshtadt et al. 2011). Such a short-term exposure is not likely to induce the formation of DNA adducts or DPX. The proliferation capacity of formaldehyde-stimulated A431 maintained higher than that of the control cells for 3 days in formaldehyde-free culturing media, and the percentage of S-phase cells increased significantly 24 h after the formaldehyde treatment. In addition, they showed that short-term 30 μM formaldehyde led to reversible actin cytoskeleton disassembly, formation of epidermal growth factor receptor patches, and increased epidermal growth factor receptor phosphorylation. Continuous cultivation for 24 h in the presence of 30 μM formaldehyde also increased the S-phase cell percentage in HEK293 and rat fibroblasts and accelerated the proliferation of the two types of cells. However, the pro-proliferation effect of 5 min formaldehyde stimulation on A431 cell was nonlinearly in a dose-dependent manner. The proliferation of A431 was inhibited when the stimulation concentration of formaldehyde was over 60 μM (Aizenshtadt et al. 2011).

In the case of formaldehyde-induced acceleration of proliferation in A375P (1-day exposure) and SK-MEL-28 cells (3-day exposure), the acute increase in extracellular-regulated protein kinase (ERK) phosphorylation was detected with 1 h formaldehyde treatment in both cell lines (Rizzi et al. 2014). The short-term effect of formaldehyde on the phosphorylation of ERK would be a molecular event that happened earlier than formaldehyde-induced DNA damage. 10 μM formaldehyde could also induce acute increase in ERK phosphorylation in spontaneously immortalized keratinocyte HaCaT cell when cell proliferation was not affected after 1-day formaldehyde treatment (Rizzi et al. 2014). ERK is a converging point of multiple signal transduction pathways involved in cell proliferation and DNA damage response (Lin et al. 2013). Thus, ERK signaling pathway is probably the initial responding pathway to formaldehyde exposure, which might lead to downstream regulation of cell proliferation and DNA damage repair.

An et al. observed that a short-term formaldehyde exposure (2 h, 75 μM, and 40 μM) significantly promoted the proliferation of K562 cells and 16HBE cells, respectively, accompanied with elevated intracellular oxidative stress (increase in reactive oxygen species (ROS) and decrease in glutathione) and cell cycle marker (CyclinD, cdk4 and E2F1) expression. The addition of vitamin E, an effective inhibitor of ROS, restored the formaldehyde-induced increase in oxidative stress and cell cycle marker expression (An et al. 2019). Although, An et al. also observed formaldehyde-induced changes in intracellular glucose and lactic acid levels, and the expression of key enzymes involved in glycolysis, further evidence is still needed to prove their hypothesis that formaldehyde increases cell proliferation by affecting the Warburg effect rather than a synergistic metabolic stress response. In addition, 10 nM–10 μM formaldehyde increased the proliferation of human choriocarcinoma cell (JEG-3) and the expression of cell cycle inducers (cyclinD and cyclinE1) while decreased the expression of cell cycle inhibitors (p21 and p27) (Lee et al. 2017). Meanwhile, the formaldehyde-induced increased ROS level was also observed. These works above showed that oxidative stress signaling is probably involved in the formaldehyde-induced pro-proliferative effect.

3.3 The Production and Accumulation of Formaldehyde in Cancer

The increased total metabolism of amino acids and nucleotides in the cancer cell promotes an increased formation of formaldehyde, which is manifested by an increased concentration of formaldehyde in tumors and in the biological fluids of cancer patients (Dorokhov et al. 2018). The urine formaldehyde concentration in the patients with prostate and bladder cancer is elevated for 2–8 fold compared with the normal participants (Spanel et al. 1999). Concentrations of formaldehyde in lung cancer (0.72 ± 0.06 mM) and breast cancer (0.75 ± 0.12 mM) tissues were significantly higher than that in the normal tissues adjacent to the tumor (0.1–0.2 mM) (Tong et al. 2010). The formaldehyde level in the expired air from tumor-bearing transgenic mice (1.43–2.98 μM) was 2–3 fold higher than the control mice (0.77–1.01 μM) (Ebeler et al. 1997). Concentrations of formaldehyde in the medium of cancer cell lines and in the ascitic fluid from mice inoculated with cancer cells gradually increase over time (Tong et al. 2010). Therefore, formaldehyde released from cancer cells and tumor tissues would provide a pro-proliferative microenvironment and probably stimulate tumor progression. Lysine-specific demethylase 1 contributes to the production of endogenous formaldehyde in cultured MRMT-1 breast cancer cells (Liu et al. 2013). Given that tumor cells are characterized as general DNA demethylation and specific DNA hypermethylation of certain genes (Kisseljova and Kisseljov 2005), Tong et al. proposed that the elevated endogenous formaldehyde level in cancer cells could also be sourced from the methyl groups dropped from the chromosome (Tong et al. 2015). Accumulation of formaldehyde in cancer cells is combined with activation of the processes of cellular formaldehyde clearance. Dorokhov et al. (2018) reviewed the sources and regulation of formaldehyde metabolism in cancer cells and proposed that balancing of formaldehyde in the body may serve as the basis of future anticancer therapy.

There was a lack of demonstration of the short-term delivery of inhaled formaldehyde to distant sites at present (Heck and Casanova 2004; Lu et al. 2010; Kleinnijenhuis et al. 2013; Salthammer 2015; Zhang et al. 2014). Exogenous formaldehyde-induced DPX (6 ppm, 2 days, 6 h/day; 15 ppm, 1–4 day, 6 h/day) was only detected in rat nasal respiratory tissues but were absent in tissues distant to the site of contact (bone marrow and liver) (Lai et al. 2016). By using N⁶-formyllysine as a biomarker of formaldehyde exposure, Edrissi et al. showed that formaldehyde forms adducts in nasal epithelium and to some extent in trachea, but not in distant tissues of lung, bone marrow, or white blood cells (Edrissi et al. 2017). Yu et al. showed that inhaled formaldehyde only reached rat (Male F344 rats, 2 ppm formaldehyde atmospheres for 7, 14, 21, or 28 consecutive days (6 h/day)) and monkey (Cynomolgus macaques, 6 ppm formaldehyde atmospheres for 2 consecutive days (6 h/day)) noses, but not tissues distant to the site of initial contact and confirmed that the amount of endogenous formaldehyde-induced DPX (dominantly N₂-hydroxymethyl-dG) was higher than that induced by the inhaled formaldehyde, suggesting that endogenous formaldehyde leads to severer DNA lesions than inhaled formaldehyde (Yu et al. 2015).

However, the exogenous formaldehyde-induced accumulation of formaldehyde in the brain is evidential. Acute high-dose formaldehyde injection could increase brain formaldehyde level. The concentration of brain formaldehyde in C57BL/6 mice acutely increased from the baseline (13 μM) to ~15 μM, 2 h after tail vein injection of formaldehyde (3.7 μg/g of body weight), and the elevation of brain formaldehyde level maintained for at least 10 h (Lu et al. 2013). Li et al. showed that the brain formaldehyde concentration significantly increased 7 days after the intraperitoneal injection of formaldehyde (0.2 μg per gram of body weight) in C57BL/6 mice (Li et al. 2016a). Seven-day exposure to vapor formaldehyde (2 ppm; 2 h/day) was found to elevate brain formaldehyde level in adult male Kunming mice (Li et al. 2016b). The formaldehyde level could be elevated even by interrupting the endogenous formaldehyde metabolism by abnormal extreme situations, such as hindlimb unloading and acute high-altitude hypoxia exposure (Yao et al. 2021; Wang et al. 2022). Since the DNA synthesis processes in most brain cells (neurons and glia cells) are largely quiescent, the elevated brain formaldehyde level is not likely to induce cancerous changes in these developed brain cells. However, given the pro-proliferation effect of low-dose formaldehyde, abnormally increased physiological formaldehyde level, for example, in the brain of senior individual and Alzheimer’s disease (AD) patients (80–200 μM) (Tong et al. 2013b), would become a potential pro-proliferation factor for metastatic cancer cells in the brain, which raises the risk of metastatic brain tumor in practice.

4 Moderate Concentration of Formaldehyde and Programmed Cell Death

Programmed cell death, particularly apoptosis, is triggered by formaldehyde in a concentration-time-dependent manner. A moderate concentration of formaldehyde induces DNA damage at a faster rate than a low concentration of formaldehyde, and leads to oxidative stress (ER stress), mitochondrial dysfunction, excitotoxicity, and proteotoxicity to cells, which all contribute to the formaldehyde-triggered programmed cell death.

4.1 Apoptosis

Formaldehyde released from its intracellular carrier (Szende et al. 1998) and sufficient concentration of formaldehyde added into the cell culture medium could enhance apoptosis. The expression of ADH3, a formaldehyde degradation enzyme, in human oral keratinocytes was lowered when cell cultures have reached full confluent (Nilsson et al. 2004), suggesting that cells autonomously increase the endogenous formaldehyde level under weakened proliferation state. Rat lymphocytes exposed to 100 μM formaldehyde for 24 h showed increased population of cells with shrinking morphology and hypodiploid DNA, reflecting the progress of apoptosis (Nakao et al. 2003). A 4 h exposure to 0.35 mM formaldehyde induces apoptosis in Calu-3 and 16HBE cell lines (Kastner et al. 2011). The presence of 0.5 mM formaldehyde or soluble semicarbazide-sensitive amine oxidase, a formaldehyde production enzyme, in the medium, induces apoptosis in rat aorta A7r5 and human aortic smooth muscle cells (Rougeot et al. 2003). The 24 h exposure of 160 μM formaldehyde induces apoptosis in human bronchial epithelial cells and overexpression of HSP70 decreased the apoptosis induced by formaldehyde (Liu et al., 2019). Three days 250 μM formaldehyde induced apoptosis in human peritoneal mesothelial cells and 2 mg/mL alpha-1 antitrypsin could attenuate the formaldehyde-induced apoptosis (Lim et al., 2020). A total of 24 h exposure to 258 μM formaldehyde induces apoptosis in human lung epithelial cells (A549) (Nazarparvar-Noshadi et al., 2020). The 24 h exposure of 150 μM formaldehyde induced apoptosis in rat embryonic cardiomyocyte cell line H9C2 and knockdown of miR-153-3p inhibits formaldehyde-induced apoptosis of H9C2 cells (Yang et al., 2021). In addition, it is necessary to be noticed that the apoptotic dose of formaldehyde also depends on the incubation time. As we have previously mentioned in Sect. 3, low concentration of formaldehyde exposure around the formaldehyde baseline is able to induce apoptosis after a long period of exposure time. Such phenomenon is also observed in animals and human subjects exposed to low concentrations of formaldehyde, for example, inhalation and occupational contact. Formaldehyde-induced apoptosis in peripheral blood lymphocytes was detected in personnel under occupational formaldehyde exposure (Jakab et al. 2010). Low-dose formaldehyde inhalation in cynomolgus macaques, 2 ppm (6 h/day), induces miRNA transcriptional changes in the nasal epithelial, and the differentially expressed miRNAs were enriched in apoptosis signaling. At high inhalation dose, 6 ppm and above, genes related to cell cycle are upregulated, and DNA repair and apoptosis were enriched in rats (Andersen et al. 2010). The numbers of apoptotic cells and oxidative damage in the lung tissue were significantly increased in young and adult rats after 6 weeks 6 ppm (8 h/day) formaldehyde inhalation (Im et al. 2006; Sandikci et al. 2009; Sul et al. 2007). Zhang et al. (2021) reviewed the role of formaldehyde in cardiovascular disease and heart development and summarized that compared to short-term exposure, long-term exposure to high concentrations of formaldehyde in pregnant women is more likely to affect embryonic development and cause heart malformations and that the toxic effect of formaldehyde on heart development may result from formaldehyde-induced oxidative stress and cardiomyocyte apoptosis.

Intraperitoneal injection of formaldehyde induces apoptosis in the brain, lung, liver, blood, and reproductive system. Two weeks after formaldehyde injection, the malondialdehyde (MDA)-related neuronal apoptosis in the prefrontal cortex of rat was recorded (Zararsiz et al. 2007). The formaldehyde-induced (0.1–20 mg/kg body weight) apoptosis in the testis and oocytes of mice is correlated with the Fas signaling pathway (Peng et al. 2010a,b; Ozen et al. 2008; Zhou et al. 2006). The formaldehyde-induced (10 mg/kg of body weight) apoptosis in the liver and kidney was delivered by oxidative damage and dysfunction in mitochondria (Bakar et al. 2015a, b). One dose of 0.5–1.5 mg/kg intraperitoneal formaldehyde injection during pregnancy days induced oxidative stress and apoptosis of cardiomyocytes in both pregnant mice and offsprings, and vitamin E supplement during pregnancy reversed the systemic and myocardial toxicity of formaldehyde (Wu et al., 2017). Three days 10 mg/kg intraperitoneal formaldehyde injection disturbs the reproductive system of male Wistar rats, exhibiting as decrease in sperm counting and motility and increase in apoptosis of germinal cells of seminiferous tubules (Afrigan et al. 2019). 30 days 60 mg/kg intraperitoneal formaldehyde injection increases the ratio of neuronal apoptosis in the CA1 area of the hippocampus and lead to decrease in cognitive performance (Morris water maze) accompanied with increased hippocampal tau hyperphosphorylation (Thr²³¹) and inflammation (Sayad-Fathi et al. 2020). By intracerebroventricular formaldehyde injection, the spacial memory and novel object recognition of rat are reduced, the formaldehyde-induced apoptosis and lipid peroxidation increase, and hydrogen sulfide (H₂S) generation in the hippocampus is detected and interestingly, H₂S attenuates formaldehyde-induced dysfunction of cognition, hippocampal oxidative damage, and apoptosis (Tang et al. 2013; Tong et al. 2013b; Li et al. 2020a, b). A 5 day nasogastric tube formaldehyde administration (40 mg/kg/day) in rabbit caused increased apoptosis in the brain, indicated by a decrease in Bcl-2 expression and an increase in active caspase-3 and Bax expressions, and the number of GFAP-positive glia cells is also increased (Arici et al. 2014). Subcutaneous formalin injection into the ventral surface of the right hind paw of rat is a common paradigm to induce periphery inflammatory pain (Tabata-Imai et al. 2014). Hu et al. confirmed that rats subjected to the inflammatory pain model developed neuronal apoptosis and upregulation of p53 in the hippocampus, suggesting that formaldehyde-induced pain would enhance the brain damage in special memory (Hu et al. 2009). Prolonged anesthesia causes widespread apoptosis in the central nervous system (CNS). Nociceptive stimulation with formalin enhances the anesthesia-induced neuroapoptosis and cognitive impairment during the synaptogenic period in the rat (Shu et al. 2012).

4.1.1 DNA Damage Repair

The accumulation of DNA adducts and DPX leads to cell cycle arrest. Excessive DNA repair burden eventually initiates the apoptosis signaling pathway and results in tissue damage, inflammation, and organ dysfunction. Two weeks formaldehyde exposure (0.5, 3.0 mg/m³; 8 h per day) increased oxidative stress, DNA damage, and immune system disorder in Male Balb/c mice (Ge et al., 2020). Oka et al. showed that Adh5-/-Aldh2E506K/E506K double-deficient mice (deficiency of formaldehyde clearance mechanisms) exhibits short lifespan, dwarfism, and hematopoietic failure due to overload of formaldehyde-induced DNA damage (Oka et al., 2020). Juarez et al. applied DNA damage repair pathway-focused siRNA screening for formaldehyde toxicity related genes in three unrelated human cell lines (SW480, U-2 OS and GM00639) frequently used in genotoxicity studies and found that four inter-related cellular pathways were involved to mitigate formaldehyde toxicity: homologous recombination, double-stranded DNA break repair, ionizing radiation response, and DNA replication (Juarez et al. 2018). Using the fission yeast Schizosaccharomyces pombe as a model organism, Anandarajan et al. showed that formaldehyde generates a variety of DNA lesions, including interstrand cross-links, DPX, and base adducts (Anandarajan et al., 2020). Yang et al. showed that formaldehyde inhibited the repair of ultraviolet (UV)-induced DNA damage via inhibition of the phosphorylation pathways of H2AX, which further enhances UV-induced cytotoxicity (Yang et al. 2019). Mai et al. found that metformin could attenuate the formaldehyde-induced DNA damage (γH2AX aggregation in HepG2 cells) by its formaldehyde scavenging effect, forming a conjugated reaction intermediate (Mai et al. 2020). Nakano et al. showed that formaldehyde treatment (200 μM, 3 h) resulted in the accumulation of chromosomal breakages which were more prominent in tyrosyl-DNA phosphodiesterase 1 deficient cells than in wild type Chicken DT40 cells (Nakano et al. 2020). Astragalus polysaccharide-induced promotion of the nucleotide excision repair pathway protects bone marrow mesenchymal stem cells from formaldehyde induced (120 μM, 24 h) cytotoxicity, DNA strand breakage, DPX, and micronucleus levels (She et al. 2021). By using nucleotide excision repair-deficient CHO cell lines, Kumari et al. observed delayed double-stranded DNA break repair in formaldehyde-treated DNA repair endonuclease XPF-deficient cells, indicating the involvement of XPF in the formaldehyde-induced genomic instability (Kumari et al. 2012). Several proteins in Fanconi anemia pathway, including FANCD2 and FANCD1/BRCA2, are essential to counteract formaldehyde-caused DPX in the Chicken B-lymphocyte DT40 cell line (Ridpath et al. 2007). Ren et al. showed that FANCD2 mediates the repair of the formaldehyde-induced DPX in human lymphoblastoid cells. A 24 h formaldehyde treatment (50–150 μM) induces more DPX production and apoptosis in FANCD2-deficient cells as compared to cells that ectopically express the FANCD2 protein (Ren et al. 2013). Ren et al. systematically evaluated the tissue responses to formaldehyde fumes in an in vitro human air-liquid-interface airway tissue model and showed that exposure to 30 ppm of formaldehyde induced sustained oxidative stress and downregulated the DNA repair enzymes MGMT and FANCD2, suggesting its possible interference in the DNA repair capacity (Ren et al. 2022).

4.1.2 Oxidative Stress and Mitochondrial Dysfunction

Formaldehyde-induced apoptosis is closely related to oxidative stress: redox enzymes and antioxidative compound were found involved in the regulation of the formaldehyde-induced apoptosis. By mimicking occupational formaldehyde exposure, using 3 mg/m³ formaldehyde in air for 2 weeks, BALB/c mice showed increasing formaldehyde-induced apoptosis in the nucleated spleen and colony-forming unit-granulocyte-macrophage, as well as increasing oxidative damages (Wei et al. 2017; Zhang et al. 2013). Formaldehyde-induced (10 nM; 9 days) apoptosis in human colorectal cancer SW620 cells is accompanied with elevated ROS (Lee et al. 2016). Yu et al. found that peroxiredoxin II gene was involved in formaldehyde-induced bone marrow apoptosis: siRNA-induced downregulation of the expression of peroxiredoxinII enhances apoptosis and increase in ROS in bone marrow cells isolated from BALB/c mice induced by 24 h of 100 μM treatment (Yu et al. 2019). Umansky et al. found that endogenous formaldehyde reacts with the redox-active thiol group of glutathione, causing oxidative stress, and subsequently triggers cellular redox imbalance in human cells and in Caenorhabditis elegans (Umansky et al. 2022). Exposure to 100 or 200 μM formaldehyde for 24 h led to increased cell apoptosis and increased ROS levels in mouse neuroblastoma cell line N2a (Yi et al. 2020). Bernardini et al. (2022) reviewed the studies on the cytotoxicity of formaldehyde from 2013 to 2019 and proposed that formaldehyde exposure induces DNA adducts and DPX, increase in ROS and repression in cellular redox enzymes subsequently leading to oxidative stress, DNA damage and inflammatory cytokine release, which eventually cause apoptosis.

Excessive oxidative damage leads to mitochondrial dysfunction. Formaldehyde induces apoptosis and mitochondrial clustering around the nucleus in rabbit corneal epithelial cells, which is attributed to the downregulation of ERK and persistent JNK activation (Lai et al. 2013). Zhang et al. indicated that formaldehyde induced apoptosis in Chinese hamster lung fibroblast (V79–4) cells by elevating intracellular ROS production and inhibiting the mitochondrial function via inhibiting the c-JNK pathway (Zhang et al. 2010b). In sensitive neuronal SK-N-SH cells, oxidative stress was induced after formaldehyde exposure (7.5–27.5 μM) for 2 h. Formaldehyde (13.5 μM, 12 h) treatment greatly reduced cellular ATP level and mitochondrial membrane potential, indicating the dysfunction of mitochondria. The treatment further caused a concentration-dependent increase in nuclear fragmentation and activated the apoptosis-initiator caspase-9 and apoptosis-effector caspase-3/caspase-7 (Zerin et al. 2015). Tang et al. confirmed that formaldehyde causes apoptosis by mitochondria-related oxidative stress in mouse neuroblastoma PC12 cell, in which the inhibition of paraoxonase-1 expression and activity was involved. They also showed neural protective effect of H₂S against the formaldehyde-induced neuroapoptosis via the brain-derived neurotropic factor (BDNF)-TrkB pathway (Jiang et al. 2015; Tang et al. 2011, 2012). Boncler et al. showed that 24 h formaldehyde incubation increased the mitochondrial membrane potential in mouse 3T3 fibroblasts (126–378 μM) and decreased the mitochondrial membrane potential in human endothelial cells (HMEC-1) (504–630 μM) (Boncler et al. 2019).

4.1.3 ER Stress

Formaldehyde-induced disturbance in redox balance would subsequently induce ER stress, indicated by the elevated expressions of the ER stress markers, glucose-regulated protein 78 and C/EBP homologous protein, and eventually apoptosis in PC12 cell. Knockout of the modulator of ER stress and inhibitor of apoptosis increased the susceptibility of PC12 cells to formaldehyde-induced neurotoxicity (Luo et al. 2012). Li et al. demonstrated that H₂S inhibits formaldehyde-induced ER stress (120 μM, 24 h incubation) in PC12 cells by upregulation of SIRT-1 (Li et al., 2014). Ginsenoside Rg1 rescued formaldehyde-induced apoptosis in SH-SY5Y, PC12, and N2a cells and suppressed formaldehyde-induced ER stress by inducing Trx-1 expression in PC12 cells (Chen et al. 2014; Luo et al. 2012; Sun et al. 2013). By using lung epithelial A549 cells, Lim et al. demonstrated that formaldehyde induces apoptosis by decreasing Prx-2 expression via p38 MAPK pathway (Lim et al. 2010). They showed that formaldehyde treatment increases the phosphorylation of ER stress proteins, IRE1alpha, PERK, and eIF-2alpha, as well as increases the expressions of pro-apoptotic proteins, such as Bax, C/EPB homologous protein, cleaved PARP, and cleaved caspase-3, but decreases the expression of the antiapoptotic protein Bcl-2. Overexpression of dimethylarginine dimethylaminohydrolase 1 reverses the formaldehyde-induced apoptosis and ER stress (Lim et al. 2013). Two weeks 10 mg/kg daily intraperitoneal formaldehyde injection induced disorganization and loss of mitochondrial cristae, and dilatation in the ER in testes of male Wistar albino rats, indicating formaldehyde would induce ER stress in vivo (Uluçam and Bakar, 2016). Interestingly, Liang et al. showed that ER stress (induced by thapsigargin) could lead to overproduction of formaldehyde in lysosomes (Liang et al. 2018).

4.1.4 Excitotoxicity

Formaldehyde would probably induce a prolonged over-excitation of the hippocampal neuron, exhibiting the excitotoxicity. This will provide another explanation for the apoptosis induced by formaldehyde (Chi et al. 2012). Chi et al. showed that 1 mM formaldehyde increases intracellular calcium concentration in primary cultured hippocampal neurons, which is an indication for neural activation. Stimulation of Ca²⁺ release-activated calcium channels was shown to trigger Ca²⁺ entry into the cells and subsequent Ca²⁺ oscillations in proliferating cells. However, sustained Ca²⁺ entry through Ca²⁺-permeable cation channels is able to trigger apoptosis (Lang et al. 2005, 2006).

4.1.5 Proteotoxicity

For the pathologic effects on non-proliferative tissues, proteotoxicity is another important factor in cell injury caused by formaldehyde. Formaldehyde could modify the cysteine residues via cysteine thiazolidination, which is anticipated to serve as a biomarker for oxidative stress and formaldehyde exposure (Liu et al. 2016). Ortega-Atienza et al. showed that formaldehyde-treated human cells rapidly accumulate large amounts of damaged proteins undergoing K48 polyubiquitination (Ortega-Atienza et al. 2016) and immunoproteasomes could inhibit the formaldehyde enhanced activation of the cytosolic protein damage (Ortega-Atienza et al. 2017). Meyers et al. found that HIF1 and HIF2 are vulnerable to formaldehyde exposure. Formaldehyde damages the HIFα subunits of the two genes and triggered cellular clearance of the damaged proteins via ubiquitin and immunoproteasome-dependent proteolysis (Meyers et al. 2022). By using genome-wide gene expression analysis (microarrays), Karengera et al. showed that Caenorhabditis elegans is sensitive to formaldehyde stimulation (1–10 mM, 4 h) and 495 formaldehyde-responding differentially expressed genes were identified, including two upregulated unfolded protein stress-related genes, DNaJ domain (prokaryotic heat shock protein), and Protein disulfide isomerase (Karengera et al., 2021). Formaldehyde could also induce Tau protein aggregation and hyperphosphorylation in vitro and in vivo, which has been demonstrated to play an important role in formaldehyde-induced cognitive impairment (see Chap. 9 for details).

4.2 Autophagy and Cell Senescence

Besides apoptosis, formaldehyde could also induce programmed cell death in the way of autophagy and cell senescence. Formaldehyde inhalation (5–10 mg/m³; 8 h/day; 4 weeks) could induce autophagy in rat testicular tissue, indicated by increased LC3-II expression in testis and Rno-circRNA-016194 might be involved in the long-term formaldehyde exposure-induced testicular injury via rno-miR-449a-5p mediated Atg4b activation (Han et al. 2015; Ge et al. 2021). Inhaled formaldehyde (4 weeks 5–10 mg/m³, 2 h/day) induces inflammation and autophagy correlated lung injury as well (Liu et al., 2018). Formaldehyde could accelerate cellular senescence in HT22 cells evidenced by the decrease in SA-β-Gal positive cells, the downregulations of P16INK4a and P21CIP1, as well as decrease in cell growth arrest, and H₂S inhibits formaldehyde-induced senescence in HT-22 cells via upregulation of leptin signaling (Zhan et al. 2016; Zhu et al., 2019). Recently, Zhou et al. developed a novel senescent cell targeting fluorescence probe, PGal-FA, using the strategy of biomarker combination triggered tandem activation with two senescence marker β-galactosidase and formaldehyde, exhibiting improved selectivity and accuracy compared to the traditional single-biomarker-based probe (Zhou et al. 2022). Nadalutti et al. showed that 250 μM formaldehyde induces mitochondrial dysfunction and stimulates activation of mitophagy/autophagy that in turn contributes to the removal of damaged mitochondria and proposed that this mechanism may be essential to overcome the effects of increased cellular levels of formaldehyde (Nadalutti et al. 2021; Nadalutti et al. 2020). Ferritinophagy, a ferritin mediated autophagy process, is a potential mechanism of neurotoxicity. Hu et al. found that formaldehyde induces neurotoxicity by promoting ferritinophagy in a nuclear receptor coactivator 4-dependent manner. 24 h 100–200 μM formaldehyde exposure upregulated ferritinophagy in the mouse hippocampal neuronal HT22 cells, while inhibition of ferritinophagy by silencing the expression of nuclear receptor coactivator 4 decreased formaldehyde-induced toxic damage. Moreover, 7 days 2.5 μL intracerebroventricular formaldehyde injection (0.1, 1, and 10 μmol) boosted the accumulation of autophagosomes in the hippocampal CA1 and CA3 region in Sprague-Dawley rats (Hu et al., 2021). Since autophagy plays an importance role in controlling the level of DPX (Mu et al. 2016), the formaldehyde-induced autophagy would probably a compensatory enhancement due to the formaldehyde-induced DPX.

5 The Acute Cytotoxicity of High Concentration of Formaldehyde

The critical concentration for the acute toxicity of formaldehyde is around 1 mM. Most cells cannot survive when incubated with the presence of formaldehyde at concentrations higher than 1 mM after certain incubation period. Such a high formaldehyde concentration disrupts the integrity of membrane and genetic materials, which results in necrosis, indicated by uncontrolled release of cell death products into the extracellular space. After 10 mM formaldehyde treatment, instant high degree of cell damage and practically eradication were recorded in human colon carcinoma HT-29 and human endothelial HUV-EC-C cell cultures (Tyihak et al. 2001). Exposure to 3.5–7.0 mM formaldehyde for 24 h leads to large amount of lactate dehydrogenase leakage in bronchial epithelial Calu-3 and 16HBE cell lines, indicating significant formaldehyde-induced necrosis (Kastner et al. 2011). Primary human NK cells exhibit shrinking in morphology and cell colony disappearance when treated with >0.4 mM formaldehyde for 1 h, indicating the acute toxicity of formaldehyde, and 1 h exposure to >1.6 mM formaldehyde leads to significant increase in necrosis and late apoptosis (Li et al. 2013). 4 h incubation with >1.25 mM formaldehyde drastically decrease the viability of human middle ear epithelial cells accompanied with significantly loss of mitochondrial membrane potential (kim et al., 2018).

Neuronal cells were more sensitive to formaldehyde. The necrosis-inducing formaldehyde concentration for neuronal cell lines is 0.2–0.5 mM, lower than that for other cancer cells. Exposure to >0.3 mM formaldehyde for 24 h reduces ~50 % of the viability of human neuroblastoma SH-SY5Y cell, and the increase in necrosis was detected (Miao et al. 2013; Song et al. 2016). Chen et al. reported that 24 h exposure to >0.2 mM formaldehyde in serum-free medium completely killed mouse neuroblastoma N2a (1 × 10⁴ cells/well) (Chen et al. 2014). The necrosis-inducing formaldehyde dose also depends on cell density. A higher seeding density could partially relieve the stress of formaldehyde on cell survival. Lu et al. showed that 24 h 0.5 mM formaldehyde only killed ~40 % SH-SY5Y cells when cells were seeded at a high density (1 × 10⁵ cells/well) under the serum-free condition. They observed the acute formaldehyde-induced morphological changes in cells but no sign of necrosis could be detected (Lu et al. 2013). When cells were allowed to grow to confluent (48 h) before formaldehyde treatment, the addition of 1 mM formaldehyde in the medium just induced apoptosis in human tumor (HT-29, SW-620, HT-1080) and endothelial (HUV-EC-C) cells instead of inducing necrosis (Tyihak et al. 2001).

6 Conclusion

Accumulating public attentions have been paid to the neurotoxicity of formaldehyde during aging and the carcinogenesis of environmental and occupational formaldehyde exposure. The cytotoxicity and carcinogenesis of formaldehyde manifestly reveal two distinct cellular functions of formaldehyde: inducing cell death and promoting cell proliferation. The cellular effect of formaldehyde is time- and dose-dependent. The effective dosages and the mode of actions of formaldehyde were summarized in Fig. 6.1. Short-term small interruption on the formaldehyde baseline, that is, formaldehyde elimination by formaldehyde capturers or addition of low-concentration formaldehyde (<0.1 mM), stimulates the proliferation of cancer cells by activating ERK pathways and raising genomic instability, which contributes to the carcinogenesis of formaldehyde. Moderate concentration of formaldehyde (0.1–1 mM) further accumulates the formaldehyde-induced DNA adducts and DPX, which overwhelm the cellular DNA repair capacity and trigger programmed cell death, especially apoptosis. In addition, moderate concentration of formaldehyde induces oxidative stress, mitochondrial dysfunction, ER stress, proteotoxicity, and excitotoxicity delivered by prolonged Ca²⁺ releasing in neurons, which subsequently lead to apoptosis. Formaldehyde plays a role in autophagy and cell senescence, as well. High concentration of formaldehyde (>1 mM) induces necrosis. Particularly, neuronal cells are more sensitive to the toxicity of formaldehyde. The necrosis-inducing formaldehyde dose also depends on cell density.

Fig. 6.1

The schematic diagram for effects of formaldehyde at different concentrations on cell proliferation and cell death. Pro-proliferation of cells could be observed in the presence of low concentrations of formaldehyde (<0.1 mM) in a short-term cultivate. Moderate concentrations of formaldehyde (0.1–1 mM) induce apoptosis. High concentrations of formaldehyde (>1 mM) promote necrosis. Low concentrations of formaldehyde treatment could trigger apoptosis, when the exposure time is prolonged enough. Cells that grow in their high density could partially attenuate the pro-necrosis effect of high concentration of formaldehyde

Acknowledgments

All grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_7

7. Gut Microbiota, Formaldehyde Dysmetabolism, and Cognitive Impairment

Kaili Liu¹, Yijie He², Beila Wen², Yan Wei³ and Rongqiao He3  

(1)

Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA

(2)

Beijing No.101 High School, Beijing, China

(3)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Formaldehyde has been shown to play important roles in contributing to age-related cognitive impairment including Alzheimer’s disease (AD) and vascular dementia (VD). Gut microbiota, also called “the second brain,” can modulate brain function and participate in pathogenesis of neurodegenerative diseases. However, whether there is a link among formaldehyde, gut microbiota and cognitive impairment remains unclear. In this review, we briefly summarized the research progress of formaldehyde and gut microbiota, and discussed their relationships with age-related cognitive impairment. We propose a probable link between gut microbiota and formaldehyde based on the probable functions of 5-HT and NE during these neurodegenerative diseases. We hypothesize that formaldehyde derived from gut microbiota may be involved in cognitive function and its dysmetabolism may be a risk factor of AD or even lead to cognitive decline. It is also intriguing to predict that, within several specific AD-related gut microorganisms reported to date, the shortage of hexulose-6-phosphate synthase (HPS)/6-phospho-3-hexuloisomerase (PHI) in these probiotics may contribute to the onset of AD and cognitive impairment. In order to clarify that dysmetabolism of formaldehyde in intestinal microbiota is involved in AD, we compared the concentration of intestinal formaldehyde in APP/PS1 double-transgenic mice and that of C57BL/6j wild-type mice. There is a significantly elevated level of formaldehyde in the cecum digestion content of the APP/PS1 transgenic mice, and so is the formaldehyde level in the small intestinal wall for the APP/PS1 transgenic mice compared to the control. In human feces, formaldehyde level is tenfold of that in urine. These data suggest intestinal microbiota is a main source of formaldehyde, which may have a link to cognitive impairment. It was observed that the intestinal length also extended from month 4 to month 24 in 129S2/SvPasCrl mice and C57BL/6 J wild-type mice. To prevent or delay the progress of neurodegeneration, it is reasonable to use formaldehyde scavengers, such as probiotics, in addition to previously proposed antioxidative and anti-inflammatory chemicals to prevent, delay, attenuate, and/or block the progress of age-related cognitive impairment, therefore improving the human health and quality of life.

Keywords

FormaldehydeGut microbiotaBrainCognitive abilityCognitive impairmentMetabolismDysmetabolismSerotoninNorepinephrineProbioticsAPP/PS1 transgenic mouseCecum digestion contentsSmall intestinal wall

Abbreviations

A

Aβ

amyloid beta

AD

Alzheimer’s disease

B

BBB

Blood–brain barrier

C

CNS

Central nervous system

D

DNPH

2,4-Dinitrophenylhydrazine

E

ENS

Enteric nervous system

Enzyme

S-(Hydroxymethyl)glutathione synthase

F

F6P

Fructofuranose-6-phosphate

Fae

Formaldehyde-activating enzyme

G

GABA

Gamma-aminobutyric acid

Gfa

Glutathione-dependent-formaldehyde-activating

Gly

Glycine

GSH

Glutathione

GSH-FDH

Glutathione-dependent formaldehyde dehydrogenase

GSCHO

S-formylglutathione

GSCH2OH

S-(hydroxymethyl)glutathione

GSK-3β

glycogen synthase kinase-3β

H

H4MPT

tetrahydromethanopterin

HCHO

formaldehyde

HPS

3-hexulose-6-P synthase

5-HT

serotonin

Hu6P

hexulose-6-phosphate

L

LTP

Long-term potentiation

M

MFA

Metaformaldehyde

N

N5,10CH2 = H4MPT

5,10-methylene-tetrahydromethanopterin

N5,10CH2 = THF

5,10-methylenetetrahydropteroyl mono-L-glutamate

NE

Norepinephrine

P

PD

Parkinson’s disease

PFA

Paraformaldehyde

PHI

6-Phospho-3-hexuloisomerase

R

Ru5P

D-ribulose-5-phosphate

RuMP

Ribulose monophosphate

S

Ser

Serine

SHMT

Serine hydroxymethyltransferase

T

THF

Tetrahydropteroyl mono-L-glutamate

THF/H4F

Tetrahydropteroyl mono-L-glutamate

1 Introduction

Formaldehyde is a naturally occurring organic compound and the simplest aldehyde existing in several distinct forms. As a gas, it is colorless with irritating odor. This gas form is able to convert to a number of other forms upon condensation. One of important derivatives is the cyclic trimer metaformaldehyde (MFA) or 1,3,5-trioxane with the formula (CH₂O)₃. One of a linear polymer form, called paraformaldehyde (PFA), is commonly used in scientific researches because of its practical value. Formaldehyde is a significant risk for human health due to its chemical activity, toxicity, and global use. Although formaldehyde has been abundantly studied, so far, a few laboratories reported formaldehyde production in human intestinal microbiota (Basile et al. 2023).

It has been generally known that there are approximately 10¹² human cells while 10¹³–10¹⁴ bacteria cells in our body, indicating that human body is actually composed of more bacteria than our own cells (O’Hara and Shanahan 2006; Whitman et al. 1998). These trillions of bacteria and other microorganisms are called the microbiota (Kim et al. 2013; O’Hara and Shanahan 2006). Most of those bacteria locate/live in human’s gut, referred to as the gut/intestinal microbiota, and they play numerous roles in human development, physiology, and pathology (Qin et al. 2010). Intestinal microbiota play important roles in physical and psychological health via their own neural network: the enteric nervous system (ENS), which is a comprehensive system composed of ~100 million nerves found in the lining of the gut (Cryan and Dinan 2012). The ENS is also called the “second brain,” and it actually arises from the same tissues as the central nervous system (CNS) during embryonic development (Cryan and Dinan 2012). Therefore, it has many structural and chemical parallels and similarities to the brain, which functions via hormones, neurotransmitters, electrical impulses, and immunoreactions (Hyland and Cryan 2016; M Hao 2016).

Previous studies indicated that widespread use of gluten and sugar in food and lack of healthy fat intake would cause the systemic inflammation, eventually attack the CNS functions, and affect the brain health (Cryan and Dinan 2012). New evidence showed that the influence of diet on brain health is not because of the diet-induced inflammatory responses but because of the disruption of gut microbiota by diet (Clark and Mach et al. 2016). Formaldehyde is also endogenously produced and metabolized in animal and human guts (Ohsawa et al. 2015; Wang et al. 2015). Furthermore, formaldehyde is easily dissolved in blood, freely crosses through blood–brain barrier (BBB), and exists in all cells including neurons and glial cells (Shcherbakova et al. 1986). It has been reported that gut microbiota influence human emotion and cognition (Finegold et al. 2010; Naseribafrouei et al. 2014). According to Hu et al., the dysregulation of gut microbiota is correlated with cognitive impairment and neurodegenerative diseases (Hu et al. 2016). Therefore, the relationships between cognitive impairment and gut microbiota “the second brain” associated with formaldehyde will be discussed in this chapter.

2 Formaldehyde Metabolism and Associated Enzymes in Microbes

2.1 Formaldehyde Assimilation

Formaldehyde is a type of simple but highly reactive compound that has a toxic impact on almost all living organisms. As formaldehyde is a key compound in one-carbon metabolisms, most organisms have their own mechanisms for its detoxification (Bruemmer et al. 2017). During the evolution, the formaldehyde detoxification system is highly developed in methylotrophic organisms, which can assimilate C1 compounds. Here, we discuss the main pathways of formaldehyde assimilation.

2.1.1 Ribulose Monophosphate (RuMP) Pathway

Methanotrophic bacteria can produce formaldehyde from the oxidation of methane and methanol. Formaldehyde is then assimilated to form intermediates of the central metabolic pathways which are subsequently used for cellular material biosynthesis (Anthony 1991). RuMP is one of the most important formaldehyde-assimilation pathways and contributes significantly to formaldehyde detoxification in methylotrophs. This RuMP pathway was first described by Quayle et al. (Johnson and Quayle 1965; Kemp and Quayle 1967; Strom et al. 1974) and can be interpreted as three main parts: fixation, cleavage, and rearrangement, among which formaldehyde assimilation is present in fixation step.

During fixation procedure, formaldehyde and RuMP are catalyzed by hexulose-6-phosphate synthase (HPS) to generate hexulose 6-phosphate (HuMP), which in turn is converted to β-D-fructofuranose 6-phosphate (FMP) by 6-phospho-3-hexuloisomerase (HPI). Genes coding HPS and 6-phospho-3-hexuloisomerase (PHI) were found in Alzheimer’s disease (AD)-related gut probiotics (such as Bifidobacterium dentium, Lactobacillus brevis, and Lactobacillus fermentum NS9) while not in other AD associated non-probiotics and pathogenic bacteria. HPS and PHI are two important enzymes unique to this RuMP pathway. HPS and PHI were two important enzymes and initially believed to be unique to the metabolism of one-carbon compounds by methanotrophs and some other methylotrophs that do not utilize methane. However, it was later reported that these proteins are also found in heterotrophs such as Bacillus subtilis, where they play a role in formaldehyde detoxification (Yasueda et al. 1999). Therefore, it is accepted to date that the RuMP pathway is a prevalent prokaryotic pathway involved in either formaldehyde fixation or detoxification. The HPS and PHI orthologs are also found in many non-methylotrophic organisms (Mitsui et al. 2003).

2.1.2 Serine Pathway

Methanotrophic bacteria are capable to use Ser pathway to assimilate formaldehyde, thus forming intermediates for biosynthesis of central metabolic pathways. During the first step of serine pathway, serine is formed from the reaction of formaldehyde with Gly. This reaction is catalyzed by serine hydroxymethyltransferase (SHMT), an enzyme that uses tetrahydropteroyl mono-L-glutamate (THF) as a cofactor. In the presence of formaldehyde, THF forms 5,10-methylenetetrahydropteroyl mono-L-glutamate (N5,10CH₂ = THF). During this reaction, the formaldehyde is transferred from 5,10-methylenetetrahydropteroyl mono-L-glutamate to the Gly, forming L-serine. Such enzyme for the assimilation of formaldehyde is found in Methylobacterium extorquens AM1 (Chistoserdova et al. 2003; O’Connor and Hanson 1975). Genes encoding SHMT were found in all AD-related gut bacteria, showing no preference between in probiotics and pathogens.

2.2 Formaldehyde Dissimilation

It is of necessity for most life forms to enable the detoxification of the highly toxic formaldehyde. In the case of methylotrophic bacteria, formaldehyde is not just a toxic compound, but also a central intermediate. Several different pathways for formaldehyde oxidation/dissimilation are known in bacteria.

Glutathione-dependent formaldehyde dissimilation/oxidation is one of the best characterized pathways. Glutathione (GSH) and formaldehyde (HCHO) can form the adduct S-(hydroxymethyl)glutathione (HMGSH or GSCH₂OH) both spontaneously and under the catalysis by S-(hydroxymethyl)glutathione synthase, which is also named GSH-dependent formaldehyde-activating enzyme. GSCH₂OH is in turn catalyzed by NAD- and GSH-dependent formaldehyde dehydrogenase (GSH-FDH) as its substrate and forms S-formylglutathione (GSCHO) (Barber et al. 1996; Ras et al. 1995; Sanghani et al. 2002).

Another formaldehyde dissimilation pathway is performed by enzymes that utilize either the cofactor tetrahydropteroyl mono-L-glutamate (H₄F) or the cofactor tetrahydromethanopterin (H₄MPT). In THF pathway, the reaction between formaldehyde and tetrahydropteroyl mono-L-glutamate is spontaneous and forms 5,10-methylenetetrahydropteroyl mono-L-glutamate. In THMPT pathway, formaldehyde-activating enzyme catalyzes the reaction between formaldehyde and tetrahydromethanopterin forming 5,10-methylene-tetrahydromethanopterin. In the methylotroph Methylobacterium extorquens AM1, formaldehyde condenses with one of the two pterin cofactors, THF or tetrahydromethanopterin and forms the methylene derivative 5,10-methylenetetrahydropteroyl mono-L-glutamate and 5,10-methylene-tetrahydromethanopterin, respectively. The reaction of formaldehyde with THF is spontaneous (Kallen and Jencks 1966; Marx et al. 2003). However, the condensation of formaldehyde with tetrahydromethanopterin is catalyzed by a formaldehyde-activating enzyme (Vorholt et al. 2000).

3 Gut Microbiota-Derived Formaldehyde and Cognition

3.1 AD-Related Gut Bacteria Encode Formaldehyde Metabolism

Since it has been reported that the imbalance of formaldehyde metabolism plays crucial roles during the aging and cognition impairment (Hua and He 2002) and endogenous formaldehyde is related to cognitive impairment including sporadic AD (Tong et al. 2016), we hypothesize that gut microbiota may affect endogenous formaldehyde metabolism and thus affect neurodegenerative disorder. We would suppose that there are two probable ways. On one hand, probiotic bacteria in AD patients may reduce its capacity in formaldehyde application and detoxification, which includes both formaldehyde assimilation and dissimilation approaches. On the other hand, the harmful microbiota/gut pathogens may increase the endogenous formaldehyde production and accumulation. Both probable situations can theoretically contribute to the genesis of neurodegeneration and cognitive impairment.

In order to prove this hypothesis, we examine whether AD-related gut bacteria mentioned above encode formaldehyde metabolism-related genes. The protein sequences of these bacteria were retrieved from “NCBI protein” (https://​www.​ncbi.​nlm.​nih.​gov/​protein). Evolutionary analyses were conducted in MEGA7 (Kumar et al. 2016) by using the Maximum Likelihood method based on the JTT matrix-based model (Jones et al. 1992). Since Escherichia coli (E.coli) is known as a common bacterium species existing in human gut (Hudault et al. 2001), we use this bacterium species to find whether these formaldehyde metabolism genes mentioned above can be retrieved from the “NCBI protein”. As a result, we found genes encoding HPS (KXG93554), PHI (WP_075700053), SHMT (WP_074522665), GSH-FDH (WP_077166504), Gfa (WP_032210276), Fae (KDZ90508), methanol dehydrogenase (KYO72479) in E.coli but not methylamine dehydrogenase. In formaldehyde dissimilation/oxidation pathways, no Gfa, GSH-FDH or Fae can be searched from (https://​www.​ncbi.​nlm.​nih.​gov/​protein) except GSH-FDH in Citrobacter rodentium (WP_012904961) and Salmonella enterica subsp. enterica serovar Typhimurium (OFB34987). These findings demonstrate that the “NCBI protein” can be effectively employed for searching formaldehyde metabolism-related genes in bacterium, and E.coli is used as a positive control in searching these genes.

We would like to discuss the involvement of gut microbiota-formaldehyde-brain cassette/axis in age-related cognitive impairment. The observations which support this viewpoint are as follows. First, the protein sequences of HPS and PHI from RuMP pathway of formaldehyde assimilation were analyzed. Probiotics such as Lactobacillus brevis, Bifidobacterium dentium, and Lactobacillus fermentum NS9 encode the genes for HPS/PHI, while other AD-related bacteria mentioned above were not found to have HPS (Fig. 7.1a) or PHI (Fig. 7.1b). It is interesting to predict that shortage of HPS/PHI in these AD-related probiotics may contribute to the onset of AD and cognitive impairment. Second, genes coding SHMT in formaldehyde serine pathway were found in all AD-related candidate bacteria mentioned above (Fig. 7.2), suggesting that there is no preference for gut probiotics and pathogens in formaldehyde assimilation. Third, formaldehyde dissimilation/oxidation enzymes such as S-(hydroxymethyl)glutathione synthase and Gfa sequences were also searched in AD-related probiotics and pathogens. No gene encoding S-(hydroxymethyl)glutathione synthase or Gfa was found except Salmonella enterica subsp. enterica serovar Typhimurium. Taken these three aspects together, it suggests that it is more probable for formaldehyde assimilation rather than dissimilation/oxidation to be a candidate factor in aging-related cognitive impairment.

Fig. 7.1

Molecular phylogenetic analysis of HPS and PHI

Molecular phylogenetic analysis of HPS (a) and PHI (b) is demonstrated by using by Maximum Likelihood method. AD-associated FA metabolism enzyme/protein sequences were used for multiple alignment. Protein accession number, protein name, and name of bacterium were shown. Methylomonas aminofaciens and Mycobacterium gastri were used as positive controls because HPS and PHI genes were firstly discovered in them. Lactobacillus brevis, Bifidobacterium dentium, and Lactobacillus fermentum are reported probiotics and contain HPS (a) and PHI (b). Salmonella enterica subsp. enterica serovar Typhimurium is probably a gut pathogenic bacteria, while role of Lachnospiraceae bacterium remains to be identified. Other AD Neither HPS or PHI genes in other AD related gut microbiota were found by searching NCBI protein and gene database till the present time. (Source: sequences referred to https://​www.​ncbi.​nlm.​nih.​gov/​protein)

Fig. 7.2

Molecular phylogenetic analysis of SHMT

Molecular phylogenetic analysis of SHMT was shown by using Maximum Likelihood method. FA metabolism enzyme/protein sequences which are related to AD associated gut microbiota were used for multiple alignment. Protein accession number, protein name, and name of bacterium were shown in the alignment diagram. SHMT protein was ubiquitously found in all AD-associated gut bacteria. (Source: sequences referred to https://​www.​ncbi.​nlm.​nih.​gov/​protein)

3.2 The Gut Microbiota in Alleviation of the Risk for Alzheimer’s Disease

Gut bacteria can communicate with the host through the microbiota-gut-brain axis dependent on the immune, neuroendocrine, and neural pathways to influence brain and behavior (Liang et al. 2015). Accumulating evidence suggests that microbiota-gut-brain axis plays a vital role in maintaining the health of the host and dysregulation of gut microbiota is closely associated with neurodegenerative disease and cognitive impairment. Probiotics are the type of commensal bacteria that offer potential health benefit and are able to decrease anxiety, depression, etc. However, intestinal pathogens are harmful and contribute to the risk of neurodegenerative disorder. Specific bacteria of intestinal microbiota are involved in the regulation of AD and cognitive impairment (Table 7.1).

Table 7.1

Candidates for AD-related FA-generating gut microbiota

Gut microbiota

Classification

Relation with AD

References

Lactobacillus fermentum strain NS9

Probiotic

Ameliorates cognitive impairment

Park et al. (2012), Wang et al. (2015)

Lactobacillus helveticus

Probiotic

Ameliorates cognitive impairment

Luo et al. (2014), Ohsawa et al. (2015)

Bifidobacteria longum

Probiotic

Ameliorates cognitive impairment

Del et al. (2000), Savignac et al. (2015)

Chlamydia pneumoniae

Pathogen

Associated with AD

Little et al. (2004), Gerard et al. (2006)

Helicobacter pylori

Pathogen

Associated with AD

Roubaud-Baudron et al. (2012a, b), Kountouras et al. (2012)

Toxoplasma gondii

Pathogen

Associated with AD

Prandota (2014)

AD is characterized by disruptions in gamma-aminobutyric acid (GABA) in AD patients (Lanctot et al. 2004). Meanwhile, recent report shows that Lactobacillus brevis and Bifidobacterium dentium, which are regarded as the probiotic gut bacteria, are able to produce GABA (Barrett et al. 2012). It suggests that Lactobacillus brevis and Bifidobacterium dentium may play a certain role in regulating AD via GABA neurotransmitter. Lactobacillus fermentum strain NS9, the probiotic bacteria, normalized the composition of gut microbiota, alleviated the ampicillin-induced inflammation in the gut and rescued ampicillin-induced memory impairment (Wang et al. 2015). This research indicates that the probiotic gut Lactobacillus fermentum strain NS9 maintains brain function and prevents mental disorder. Similarly, Lactobacillus helveticus has been shown to be useful for the prevention of AD and enhancing learning and memory in human (Luo et al. 2014) and mice (Ohsawa et al. 2015). Bifidobacteria longum can improve the learning and memory, and has a positive influence on cognition (Savignac et al. 2015).

3.3 The Gut Microbiota in Aggravation of the Risk for Alzheimer’s Disease

Many gut pathogens display harmful impacts in gut inflammation production and brain function, and may induce neurodegenerative disorder. These AD-related candidate gut microbiota include Chlamydophila pneumonia (Gerard et al. 2006; Little et al. 2004), Helicobacter pylori (Roubaud-Baudron et al. 2012b), Toxoplasma gondii (Prandota 2014), Salmonella enterica subsp. enterica serovar Typhimurium (Sekirov et al. 2008), and Lachnospiraceae (Minter et al. 2016). A case–control study showed that AD patients infected with Helicobacter pylori displayed lower scores in MMSE and more serious cognitive impairment (Roubaud-Baudron et al. 2012a). Additionally, the eradication of H. pylori in AD patients can prolong AD patient lifetime, suggesting that H. pylori infection may participate in the pathogenesis of AD (Kountouras et al. 2012).

For another example, amyloid deposits resembling plaques in AD brains were formed in the brains of mice following intranasal infection with Chlamydia (Chlamydophila) pneumoniae (Little et al. 2004). Chlamydophila pneumonia was found in astrocytes, microglia, and neurons of AD patients as host cells. These infected cells showed in close proximity to both neuritic senile plaques and neurofibrillary tangles in the AD brain (Gerard et al. 2006). These findings suggest that the pathogen from gut microbiota might play certain role in the neuropathogenesis of AD.

Toxoplasma gondii is an intracellular protozoan infecting 30–50% of global human population. Recently, it has been reported that chronic latent neuroinflammation caused by the parasite may be responsible for the development of several neurodegenerative diseases, including AD. Studies found that serum anti-T. gondii immunoglobulin G antibody levels significantly increased in AD patients, suggesting a link between AD and T. gondii infection (Prandota 2014). A recent work investigated the function of the host microbiome in regulating amyloidosis in a mouse model of AD and found that in ABX-treated APPSWE/PS1ΔE9 mice, a dramatic expansion of the genus Akkermansia and family Lachnospiraceae was observed, suggesting a link between these gut bacteria and AD, although the mechanism remains unknown (Minter et al. 2016).

4 Formaldehyde and Age-Related Cognitive Impairment

4.1 Dysmetabolism of Formaldehyde Related to Amyloid β Deposition and Tau Hyperphosphorylation

Oral administration of methanol (the metabolic precursor of formaldehyde) is a long-term trigger for the formation of senile plaques (SPs) and Tau hyperphosphorylation in the brains of monkeys with memory decline (Yang et al. 2014). Intraperitoneal injection of formaldehyde results in hyperphosphorylation of Tau in wild-type mouse brains and N2a cells via activating glycogen synthase kinase-3β (GSK-3β) (Lu et al. 2013a). Furthermore, formaldehyde at low concentrations can directly induce Tau aggregation and amyloid β (Aβ) peptide deposits in vitro (Lu et al. 2013b). Formaldehyde-induced Tau aggregation is implicated in cytotoxicity and neural cell apoptosis. These previous data showed that dysmetabolism of endogenous formaldehyde is closely related to age-related cognitive impairment.

In order to provide direct evidence to explain the relationship among formaldehyde, gut microbiota, and AD, we use the APP/PS1 double transgenic mice to detect the formaldehyde concentration/level in the mice gut. Guts from APP/PS1 and C57 wild-type mice were segmented, and duodenum, small intestine, large intestine and cecum were collected. Feces from small intestine, large intestine, and cecum were also sampled. Formaldehyde level determination was conducted according to the method described by Su et al. (2011) which is as follows.

4.2 Markedly Elevated Formaldehyde in the Cecum of APP/PS1 Mouse

Liu et al. compared the concentration of intestinal formaldehyde between APP/PS1 transgenic mouse and C57BL/6j wild-type mouse. Their study was on the basis of these observations: (1) Intestinal microbiota affects the function of central nervous system through the “microbiota-gut-brain axis” (Cryan and Dinan 2012). (2) Alzheimer’s disease is related to the microbiota in the intestines (Seo and Holtzman 2024; Patil and Tupe 2024). (3) The concentration of endogenous formaldehyde is positively correlated to the cognitive impairment of AD patients (Tong et al. 2011). (4) Formaldehyde can quickly enter humans, including crossing BBB (Shcherbakova et al. 1986). (5) APP/PS1 transgenic mouse is widely employed in the study of age-related cognitive impairments, in particular of AD (Bilkei-Gorzo 2014).

The duodenum, small intestine, cecum, and colon were taken and sectioned from APP/PS1 transgenic mice and C57BL/6j wild-type mice, respectively. The digestion contents and intestinal walls were sampled, and the concentrations of formaldehyde were measured with high-pressure liquid chromatography (HPLC) coupled with 2,4-dinitrophenylhydrazine (DNPH) absorbance. As shown in Fig. 7.3, the levels of the cecum formaldehyde in the digestion contents of APP/PS1 transgenic mice were significantly (P = 0.036) higher than those of C57BL/6j wild-type mice. No significant (P > 0.05) difference could be observed in the small intestine and colon.

Fig. 7.3

Comparison of concentrations of formaldehyde in the intestinal digestion contents between APP/PS1 transgenic mice C57BL/6 J mice

Concentrations of formaldehyde in small intestine, cecum and colon of APP/PS1 and C57BL/6 J mice were determined with HPLC-coupled with DNPH absorption measurements. The levels of the cecum formaldehyde of APP/PS1 mice (n = 8) were significantly (P < 0.05) higher than C57BL/6 J wild-type mice (n = 9) used as control. However, levels of formaldehyde in small intestine and colon between both APP/PS1 and C57BL/6 J mice were not markedly different (P > 0.05). (Data were reprinted with permission from Microbiology China (Liu et al. 2017))

To demonstrate formaldehyde produced by intestinal microbiota is absorbed into intestines, Liu et al. analyzed the aldehyde concentration in intestinal walls. As shown in Fig. 7.4, except for the small intestine, formaldehyde in the duodenum, cecum, and colon walls was not significantly different. In other words, formaldehyde was observably (P = 0.052) elevated in small intestinal wall, suggesting that small intestines may also absorb formaldehyde produced by microbiota (Liu et al. 2017). Intestinal microbiota is one of the important sources producing formaldehyde. The elevated concentrations of formaldehyde in the cecum digestion contents and small intestinal wall of APP/PS1 transgenic AD mice indicate that dysmetabolism of formaldehyde in the intestinal microbiota may be involved in age-related cognitive impairment.

Fig. 7.4

Concentrations of formaldehyde in the intestinal wall of APP/PS1 transgenic mice

The experimental conditions were the same as those described in the Materials and Methods section, except that the concentrations of formaldehyde in the intestinal wall were determined. Levels of formaldehyde in small intestinal walls of APP/PS1 and C57BL/6 J mice were observably different (P < 0.052). However, levels of formaldehyde in the duodenum, cecum, and colon walls were not significantly different (P > 0.05). (Data were reprinted with permission from Microbiology China (Liu et al. 2017))

4.3 Changes in Intestinal Length of Mice from Adulthood to Agedness

The intestinal microbiota markedly change with aging (Du et al. 2021; O’Toole et al. 2015; Parker et al. 2022). However, it is interesting to know what will occur in the intestines themselves, for instance, the intestinal length of a mammalian animal as aging? As described previously in this laboratory, the intestines of 129S2/SvPasCrl mice were characteristic in length changing from adulthood to agedness (Mou et al. 2021). The intestinal length became longer determined during the mice aged from month 2 to month 24, or from month 4 to month 24 also. The change of intestinal length seems to be associated with body weight. Further observation showed a similar change for C57BL/6 J wild-type mice from 2 months old to over 2 years old (unpublished data). Whether microbiota influence intestinal length needs further investigation (Fig. 7.5).

Fig. 7.5

Changes in the intestinal length during aging of mice

The intestines of 129S2/SvPasCrl mice were characteristic in length changing from adulthood to agedness, and so were the C57BL/6 J wild-type mice from 2 month old to over 2 year old. (Authors’ unpublished data)

4.4 Age-Related Cognitive Impairment May Be Related to Formaldehyde Dysmetabolism of Intestinal Microbiota

Now, there may be a potential link between formaldehyde and gut microbiota, as well as cognitive impairment. First, formaldehyde is a gaseous and water-soluble molecule that can be produced in eukaryotic cells and bacteria (Marx et al. 2003; Vorholt et al. 2000). Second, gut microbiota has been reported to modulate brain function and dysfunction (Mayer et al. 2014). Third, a series of work from this lab show that formaldehyde dysmetabolism, that is, the accumulation of formaldehyde along with aging, is closely related to the pathogenesis of AD (Tong et al. 2013). Clinical evidence shows that the degree of cognitive impairment of AD patients is positively correlated with formaldehyde levels in human urine and brain (Tong et al. 2011). These data showed that the relation between imbalance of formaldehyde metabolism and age-related cognitive impairment may result from dysmetabolism of intestinal microbiota.

In this laboratory, we recruited 30 participants at different ages (18–68 years) and their morning urine (n = 30) and feces (n = 30) were taken before breakfast. Then, aliquots were taken and quantitatively analyzed by high-pressure liquid chromatography (HPLC) as described (Chap. 17). The average concentrations of formaldehyde and acetaldehyde in urine were 26.55 ± 3.36 and 15.9.41 ± 1.31) μmol/L, respectively. The average concentrations of formaldehyde and acetaldehyde in feces were 361.50 ± 33.03 and 414.58 ± 25.21 μmol/g, respectively, which are tenfold compared with those in urine. No significant difference in the levels of the two aldehydes was detected between male and female. However, urine formaldehyde levels of the old participants (over 60 years) were higher than those of the young (~30 yrs), but no marked difference of acetaldehyde levels in urine and feces as well as formaldehyde in feces between the ages. These data suggest the higher concentrations of methanol, formaldehyde, ethanol and acetaldehyde produced by intestinal microbiota in feces than those in blood. As we know, those aldehydes and alcohols can be easily absorbed into bloodstream (Zakhari 2006).

4.5 Administration of NS Lactobacillus as a Try

As described by Martínez et al., gut microbiota in elderly’s health will enable intervention through probiotics (Martínez et al. 2014). The pleiotropic actions of resveratrol may be resulted from its altering gut microbiota and influence stem cell proliferation and differentiation (Diaz-Gerevini et al. 2016). As we know, acetaldehyde dehydrogenase (EC 1.2.1.10) catalyzes both acetaldehydes and formaldehyde. To test whether NS lactobacillus can metabolite formaldehyde, I tried to drink alcohol instead because elevation of metabolism of ethanol implies an increase in metabolism of formaldehyde.

Fortunately, Jin and his group (Institute of Psychology, Chinese Academy of Sciences in Beijing) studied the lactobacillus as food nutrition for oral intake. They believed that lactobacillus is beneficial to elderly’s brain function through regulation of gut microbiota (Hu et al. 2016). Jin gave me a bag of “NS.8 + 9” lactobacillus. In order to make a sense, I (the corresponding author) have tried to take his NS lactobacillus (1 capsule, once daily) for 2 weeks. Before taking the NS capsule, I purchased 42% of commercial alcohol made from highland barley (Laochenfengtan, Huzhu county, Qinghai, China). I drank it in the dinner on each Saturday for 3 weeks. The conditions: I drank just myself, from 18:30 to19:30 each Saturday, with the same food at home. The requirement: I should not feel the effect of alcohol after 3 hours I had drank.

Afterward, I had taken the NS capsule for 2 weeks. I had not got any marked changes except for a mild diarrhea in the first week. Under the same conditions, I drank the alcohol on each Saturday for 3 weeks. Preliminarily, I found myself having a change that I was able to drink more alcohol from ~60 to ~90 mL of the alcohol with a measuring cylinder. It appears that NS lactobacillus could enhance the detoxicity of the aldehyde. It was said that some other people also had got the same effects. However, this was just a try and subjective experience to provide a preliminary record, but not a result from the formally scientific investigation.

Probiotics as an intervention to formaldehyde metabolism could be used to those elderly whose endogenous formaldehyde levels are significantly detected higher than their age-match controls. In fact, more experiments on animals and the long-term investigation of large population should be carried out to clarify whether probiotics could be beneficial to our brain and cognitive ability through gut-microbiota-brain axis. Or more rigorous, detailed, and longtime investigations should be performed to demonstrate whether administration of probiotics including the bacterial clearance of formaldehyde can mitigate the onset and progression of age-related cognitive impairment.

5 Relations of Formaldehyde Dysmetabolism, Neurodegenerative Diseases, and Gut Microbiota

5.1 Formaldehyde, Serotonin (5-HT), and Norepinephrine (NE)

AD is associated with chronic dehydration, and one of the significant changes that are known to result in metabolic dysfunction is an increase in the endogenous formaldehyde level. The brain formaldehyde levels of mice increased with age, and these increases were followed by decreases in their drinking frequency and water intake (Li et al. 2016a). Additionally, the decrease of serotonin (5-HT), but not other neural transmitters such as acetylcholine or dopamine, in brain of mice was observed, compared with control mice (Li et al. 2016a). Moreover, injection of formaldehyde results in serotonin decline and learning and memory defect indicated by shuttle-box avoidance test, suggesting the specificity of this serotonin in AD pathogenesis.

Hippocampal norepinephrine (NE) exists as a neurotransmitter that is required for learning and memory, and affects long-term potentiation (LTP) in hippocampus (Gray and Johnston 1987; Izumi and Zorumski 1999). Recently, Mei et al. reported that aging-associated formaldehyde-induced norepinephrine deficiency leads to age-related memory decline and cognitive impairment, suggesting that NE is one of the factors that link formaldehyde and AD during aging (Mei et al. 2015). Additionally, formaldehyde exposure promotes anxiety- and depression-like behaviors, such as open field test, elevated plus-maze test, and forced swimming test (Li et al. 2016b). In addition, gaseous formaldehyde inhibits tyrosine hydroxylase (TH) (Li et al. 2016b), a rate limiting enzyme for L-DOPA, the precursor of dopamine, which in turn gives rise to NE. Although it shows that formaldehyde can interact directly with NE with a yet unknown mechanism (Mei et al. 2015), it is clearly believed, at least, that formaldehyde may affect cognition via inhibiting TH-DA-NE cassette. This is to say, 5-HT and NE are two specific markers in formaldehyde-derived AD pathogenesis, and formaldehyde increment-related behavior and cognitive impairment may be caused by its inhibitory regulation on 5-HT and NE.

5.2 Gut Microbiota, Serotonin (5-HT), and Norepinephrine (NE)

Serotonin (5-Hydroxytryptamine, 5-HT) is a fundamental and common transmitter in neural physiology and brain activity. More than 95% of the 5-HT are generated in the gut, and thus gut microbiota should be the most important contributor for the synthesis of 5-HT (Spohn and Mawe 2017). According to Yano et al., the content of 5-HT in the blood of germfree (GF) mice was about 60% lower than that of the specific pathogen free (SPF) mice with a normal gut microbiota, and the concentration was significantly increased when the gut microbiota was reconstructed in GF mice (Yano et al. 2015). Matsumoto et al. have analyzed the influence of gut microbiota on cerebral metabolism through assessing the cerebral metabolome of GF mice and Ex-GF mice which were colonized with fecal microbiota obtained from SPF mice (Matsumoto et al. 2013). Results showed that 10 from 38 metabolites with significant changes in concentrations between GF mice and Ex-GF mice were reported to be involved in brain function. The concentrations of tryptophan (Trp), the precursors of 5-HT, were lower in the cerebrum of GF mice than that of Ex-GF mice (Matsumoto et al. 2013). The animal and human clinical trials have showed that selective serotonin reuptake inhibitors (SSRIs) could reduce the Aβ protein production in the brain. The increase extracellular 5-HT levels can effectively reduce Aβ plaque formation and thereby decrease the risk of AD (Cirrito et al. 2011). These also indicate that the changed 5-HT biosynthesis caused by gut microbiota disturbance may affect the pathological process of AD.

As described by Oleskin et al. (Oleskin and Shenderov 2016), gut microbiota can produce neurotransmitters and neuropeptides. For example, spore-forming microbes can produce 5-HT (Shishov et al. 2009), and Escherichia and Bacillus produce norepinephrine (Shishov et al. 2009; Tsavkelova et al. 2000). Recent report showed that gut microbiota play a critical role in the production of biologically active catecholamines, which include dopamine (DA) and norepinephrine (NE) (Asano et al. 2012). Results also showed that L. helveticus NS8 improves chronic restraint stress-induced behavioral (anxiety and depression) and cognitive dysfunction, and causes the restoration of hippocampal serotonin (5-HT) and norepinephrine (NE) levels in rats. This gut bacterium has an antidepressant effect, which could be due to the microbiota-gut-brain axis. It is interesting to think of the opposite phenomenon in formaldehyde stress, which reduced the 5-HT and NE levels. Also, it is intriguing to test whether the L. helveticus NS8 can be used to treat formaldehyde stress-related aging and cognitive impairment.

5.3 Upstream Regulators and Downstream Targets of Formaldehyde Involved in Neurodegeneration and Cognitive Impairment

In recent years, our formaldehyde research group not only developed a more sensitive fluorescence method for formaldehyde detection (Ai et al. 2019b), but also expanded the explorations of mechanistic studies in endogenous formaldehyde metabolism/dysmetabolism, and therefore identified and confirmed the functions of formaldehyde upstream regulators and downstream targets involved in neurodegeneration and cognitive loss. For example, we found that endogenous formaldehyde, acting as a memory-related molecule, regulated learning and memory via the N-methyl-D-aspartate (NMDA) receptor (Ai et al. 2019a). In particular, raised formaldehyde levels facilitate spatial memory formation by augmenting N-methyl-D-aspartate (NMDA) currents via the C232 residue of the NMDA receptor, as a newly identified formaldehyde target. However, high formaldehyde concentrations gradually inactivated the receptor by cross-linking NR1 subunits to NR2B (Ai et al. 2019a). In this work, formaldehyde generation and accumulation were regulated by two upstream molecules mitochondrial sarcosine dehydrogenase (SARDH) and aldehyde dehydrogenase-2 (ALDH2). In a more recent work, we reported that endogenous formaldehyde was essential for Aβ self-aggregation and degradation of formaldehyde was able to reduce Aβ neurotoxicity and Alzheimer-related phenotypes (Fei et al. 2021). In this report, amyloid-beta protein (Aβ) induced formaldehyde generation and formaldehyde cross-linked with the lysine28 residue in the β-turn of Aβ monomer to form Aβ dimers, suggesting that a feedback exists between interaction of Aβ and formaldehyde. It also implicated that Aβ behaved as both formaldehyde upstream regulators and downstream targets. Moreover, this conclusion was validated, at least partially, in no-human primate, that formaldehyde increased in the CSF of rhesus monkeys with aging and a negative correlation was found between formaldehyde and Aβ concentrations in aged rhesus monkeys (Li et al. 2020).

In parallel, a series of recent work in blood stem cell studies from other formaldehyde research groups reported that endogenous accumulation of formaldehyde, due to loss-of-function of its upstream detoxifying enzymes cytoplasmic alcohol dehydrogenase 5 (ADH5) and mitochondrial aldehyde dehydrogenase 2 (ALDH2), could lead to failure of hematopoietic progenitor production (Mu et al. 2021), shorten lifespans and develop leukemia in mice and human (Dingler et al. 2020), cause DNA damage response defects in Fanconi Anemia (Shen et al. 2020), and a multisystem disorder, AMeD syndrome (Oka et al. 2020). Another work in formaldehyde-related neurodegeneration and kidney disease (Cockayne syndrome) also demonstrated that formaldehyde could drive transcriptional stress that triggers an anorexic DNA damage response (Mulderrig et al. 2021). Moreover, a recent work in human cells and in Caenorhabditis elegans showed that formaldehyde could trigger cellular redox imbalance by reacting with the redox-active thiol group of GSH as its target, therefore leading to the GSH:GSSG ratio alteration and oxidative stress. This formaldehyde cytotoxicity could be prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR) (Umansky et al. 2022).

Taken together, these findings revealed in blood and immune system are also in agreement with the molecular mechanisms we investigated in nervous system. In addition, we presumed that more formaldehyde regulators and targets will be identified in the future beyond nervous system and immune system, since endogenous formaldehyde played known and yet unknown roles in epigenetic regulation, especially in the methylation and demethylation of DNA, histones, and RNA (Li et al. 2021).

5.4 Neurodegenerative Diseases and Gut Microbiota

Although many recent studies have shown that the gut microbiome plays important roles in human physiology and pathology, the exact relationship between neurodegenerative diseases and gut microbiota remains unclear (Wu et al. 2021). A clinical trial carried out on AD patients showed that amyloid-positive patients owned a higher abundance of Escherichia/Shigella and a lower abundance of Eubacterium rectale and Bacillus subtilis in their stools compared to other groups, indicating the role of both amyloid and relevant bacterial accumulation in cognitive impairment (Cattaneo et al. 2017). A possible explanation was that some representative components of the gut microbiota, such as E. coli and B. subtilis, can secrete large amounts of lipopolysaccharides (LPS) and amyloid proteins, which may directly pass through the gut barrier or blood–brain barrier damaged neurodegenerative disorders, and/or conducted an indirect effect to pass through these protective physiological barriers by lipopolysaccharide and amyloid-induced generation of pro-inflammatory cytokines that contribute to the development of AD (Jiang et al. 2017). Since the microbiome of the AD elderly people shows a lower proportion of bacteria synthesizing butyrate that possesses anti-inflammatory activity and immunity regulation, there is a potential therapy of AD to modulate intestinal homeostasis by decreasing inflammatory, and increasing anti-inflammatory, microbial metabolism (Haran et al. 2019). Moreover, new research have found that the tau pathology, amyloidosis, and cognitive impairment in AD mice can be ameliorated by fecal microbiota transfer therapy (Kim et al. 2020).

Gut microbiota metabolites may induce pro-inflammatory immune cell responses in intestines and result in intestinal inflammation and even the development and pathogenesis of PD (Campos-Acuña et al. 2019). It was shown that lower levels of the intestinal hormone ghrelin, which is involved in regulating the activity of nigrostriatal dopamine, were related to elevated abundance of Lactobacillaceae and decreased abundance of Prevotellaceae in the gut microbiome (Caputi and Giron 2018). Since the Gram-negative Prevotellaceae were involved in induced mucin synthesis in the intestinal mucosal layer, a decreased abundance of Prevotellaceae may lead to reduced mucin synthesis and increased intestinal permeability, leading to more exposure to microbial antigens and endotoxins, which may stimulate excessive α-syn expression in the gut and even in the brain (Mulak and Bonaz 2015). Moreover, osteocalcin was able to ameliorate the dopaminergic neuronal and the motor deficits and in PD mice through increasing the potential of microbial propionate production and activating free fatty-acid receptor 3 in enteric neurons (Hou et al. 2021).

A clinical study for amyotrophic lateral sclerosis (ALS) patients demonstrated that gastrointestinal symptoms occurred earlier than neurological symptoms, and assays of feces showed that ALS patients had lower intestinal microbiota diversity than that in healthy controls (Spielman et al. 2018). It has been hypothesized that intestinal barrier dysfunction may facilitate the entry of toxins from the intestinal lumen to the blood, leading to an increase in circulating lipopolysaccharides (LPS) and an innate immune response, which plays a critical role in the pathogenesis of ALS (Fang 2016). This is a shared potential mechanism that is similar in above-mentioned AD, PD, and ALS. A recent study reported that nicotinamide, a metabolite derived from the gut microbiome, is systemically reduced, including in the cerebrospinal fluid, in patients with ALS. Moreover, nicotinamide supplementation improved motor symptoms and modulated gene expression in ALS mouse models, indicating its potential therapeutic role (Blacher et al. 2019).

Huntington’s disease (HD) is one of the most fatal inherited neurodegenerative diseases without effective drug treatment (Bilal et al. 2024). Clinical studies in HD have reported that a different serum metabolic profile was originated from gut microbe-derived metabolites and existed in pre-symptomatic HD subjects and early symptomatic HD subjects, when compared to controls, demonstrating a potential role for the microbiome in the progression of HD (Tremlett et al. 2017). A recent multi-omics analysis of HD mice suggested that the gut microbiome regulated the pathogenesis of HD by affecting the plasma metabolites (Kong et al. 2021). Overall, these reports may provide useful biomarkers for the onset, development, and phenotypic adaptability of HD in clinic.

5.5 High-Throughput Techniques and Bioinformatics Analysis Tools for Studies of Formaldehyde Metabolism, Cognitive Impairment, and Gut Microbiome

Lately, high-throughput sequencing techniques and bioinformatics analysis methods and tools deliver a powerful means to dissect and understand the roles of the human microbiome in health and disease, also pointing out its potential as a target for therapeutic intercessions. These various techniques related to microbiome studies contain shotgun sequencing technologies, 16S rRNA sequencing, metabolomics, metagenomics, meta-transcriptomics, and multi-omics integrative analysis. (Zhu et al. 2021; Tilocca et al. 2020).

Single-cell RNA sequencing (scRNAseq) technologies have profoundly revolutionized transcriptomic studies and allowed the dissections of gene expression profile at single-cell resolution (Aldridge and Teichmann 2020). For example, scRNAseq’s recent advances and applications in the neurodegeneration and cancer research have initiated the findings of cell-type-specific changes regarding neurodegenerative diseases (Leng et al. 2021; Mathys et al. 2019; Schirmer et al. 2019) and tumor microenvironment (Hoover et al. 2022; Liu et al. 2022; Ren et al. 2021). In a recent formaldehyde study, the author used scRNAseq and identified the transcriptome of 106,531 cells from regions in the nephron that are susceptible to transcriptional stress induced by formaldehyde accumulation (Mulderrig et al. 2021). By using this method, a subset of GDF15-expressing proximal tubule cells damaged by formaldehyde induced transcriptional stress were also characterized (Mulderrig et al. 2021). In another formaldehyde research of hematopoietic stem cells (HSCs), the author analyzed the composition and transcription profiles of HSCs in WT, Aldh2−/−, Adh5−/− and Aldh2−/−;Adh5−/−dKO mice by using scRNAseq and revealed the cellular landscape modeled by disrupted formaldehyde metabolism (Dingler et al. 2020). We expect that more formaldehyde dysregulated cellular changes and gene expression changes in aging and neurodegeneration can be revealed by single-cell-based omics methodologies and more advanced bioinformatics analysis such as machine learning in the future (He et al. 2022).

6 Perspectives

In this review, we summarized the research progress of gut microbiota and formaldehyde in AD and cognitive impairment and proposed a link between gut microbiota and formaldehyde based on the probable functions of 5-HT and NE during neurodegeneration. As shown in Fig. 7.6, the gut bacteria formaldehyde assimilation and dissimilation pathways may contribute to both the physiology and pathology processes of neurodegeneration, including AD, by regulating neural behaviors through 5-HT and norepinephrine (Kato et al. 2006; Li et al. 2016b; Marx et al. 2003; Mei et al. 2015; Vorholt et al. 2000), respectively. Since formaldehyde is increasingly becoming one of the dominant factors that contribute to AD pathogenesis, we hypothesize that gut microbiota derived formaldehyde may be involved in cognition, and its dysmetabolism may be a risk factor of AD or even lead to cognitive decline. Seven-month-old APP/PS1 transgenic mouse has got its intestinal formaldehyde significantly elevated in the cecum digestion contents, compared with the C57BL/6j wild-type mouse as a control. Furthermore, the formaldehyde level in the small intestinal wall for the APP/PS1 transgenic mice is also higher than that of the control. These data suggest intestinal microbiota that is an important source of formaldehyde suffer from dysmetabolism in the AD mouse model. Imbalance of intestinal formaldehyde metabolism by gut microbiota may have a link to cognitive impairment.

Fig. 7.6

Overview of formaldehyde metabolism and its role in AD pathogenesis

Schematic diagram of gut microbiota derived formaldehyde metabolism and the regulatory roles in AD pathogenesis. The gut/gastrointestinal tract, which contains an environment of microbes and is also called the second brain, can generate endogenous formaldehyde

By using the NCBI Protein sequences to date and analyzing the genes encoding enzymes within formaldehyde assimilation and dissimilation pathways in bacteria, it is interesting to find and predict that, within several specific AD-related gut microorganisms, the shortage of HPS/PHI in these AD-related probiotics may contribute to the onset of AD and cognitive impairment while other formaldehyde metabolism-related genes may not be key factors. Nonetheless, this insight of formaldehyde’s contribution to AD derived from gut microbiota has to be validated by experiments in the future. Moreover, to prevent or delay the progress of neurodegeneration, it is reasonable to use formaldehyde scavenger or related antioxidative chemicals or anti-inflammatory drugs or probiotics to attenuate and block the reactions that lead to progress and development of the neurodegenerative diseases.

We also summarized the recent research progress of the mechanistic investigations regarding to formaldehyde upstream regulators and downstream targets in learning and memory, neurodegeneration, and blood stem cell function and diseases. We discussed the relations among formaldehyde, cognitive impairment, and gut microbiota and emphasized the emerging advanced sequencing techniques and single-cell methodologies for formaldehyde biology studies.

Acknowledgement

Many thanks to the “NCBI Protein” (https://​www.​ncbi.​nlm.​nih.​gov/​protein) for the information of enzymes involving formaldehyde metabolism. All the grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_8

8. Multifunctional Protein Tau Aggregation and Cytotoxicity

Xia-ping He1 , Yang Lu2  and Rongqiao He3  

(1)

School of Basic Medical Sciences, Dali University, Dali, Yunnan, China

(2)

Thermo Fisher Scientific Inc., Beijing, China

(3)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

 Contributed equally

Abstract

The human body, including the brain, produces and processes formaldehyde all the time. Formaldehyde is active in the reaction with biomacromolecules, especially with proteins. So, neuronal proteins have chances to react directly with formaldehyde. Among the proteins, neuronal Tau is extremely prone to react with formaldehyde because Tau features in “wormlike” conformation, and its α−/ε-amino groups are exposed to the protein exterior. Tau is a multifunctional protein which is able to bind to microtubule, actin, DNA, and RNA, with its proline-rich domain and microtubule-binding domain (MBD). Tau promotes the melting temperature of double-stranded DNA and accelerates refolding of denatured DNA. Interaction between Tau and DNA forms a complex called “DNA-Tauosome,” which may be the structure in resistance to the attack of free radicals, for example, reactive oxygen species (ROS). Treatment with formaldehyde inactivates Tau protein in the interaction with microtubule as well as DNA in which the formation of DNA-Tauosome is inhibited. In terms of the interaction between Tau protein and RNAs, it is reflected in phosphorylated protein-induced RNA accumulation, or RNA-induced protein accumulation, or interaction, so as to explore ways to prevent their accumulation and explore the treatment. Formaldehyde induces Tau aggregation which features in globular-like deposits stained with Congo red and probed by the fluorescence of thioflavin T (ThT). The cytotoxicity of globular-like aggregate leads to the impairment of cell viability and eventually to cell death. Abnormal lysosomes increase as aging and so does endogenous formaldehyde. Dysfunction of lysosome and formaldehyde metabolism could be the major risk factors to impede the cellular degradation and scavenging of protein aggregation since lysosome is one of organelles for endogenous formaldehyde to be localized. Formaldehyde is actively and directly reacted with the side chains such as amino group and thial group of peptides and proteins, In this chapter, we mainly discuss the effect of chemical modification with formaldehyde on morphology and function of neuronal Tau, except for phosphorylation, glycosylation, and other modifications. The mechanism of formaldehyde-induced cognitive impairment involves the dysfunction of NMDA receptors caused by direct binding of formaldehyde to NMDA receptors or by inducing Tau hyperphosphorylation and Aβ deposition. Formaldehyde also interacts with monoamine neurotransmitters, resulting in the inactivation of neurotransmitters such as catecholamine and serotonin, which contribute to understanding of the dysfunction of synaptic transmission, as well as cognitive impairment.

Keywords

FormaldehydeTauProtein aggregationAggregate cytotoxicityDNA-TauosomeActinMicrotubuleAbnormal lysosome

Abbreviation

Aβ

β-Amyloid

AD

Alzheimer’s disease

AFM

Atomic force microscope

ANS

8-Anilino-1-naphthalenesulfonic acid

AO

Acridine orange

BRET

Bioluminescence resonance energy transfer

BSA

Bovine serum albumin

Cur-Art

Curcumin-Artemisinin

DPCs

DNA-protein cross-links

DSS

Disuccinimidyl suberate

EFE II

Earthworm fibrinolytic enzyme II

EM

Electron microscopy

EMSA

Electrophoretic mobility shift assay

F-actin

Actin filaments

FFPE

Formalin-fixed paraffin-embedded

G-actin

Actin monomers

GDH

Glutamic dehydrogenase

GdnHCl

Guanidine-HCl

GSIS

Glucose-stimulated insulin secretory function

hTau

Human neuronal Tau

hTau-40

Human neuronal Tau-40

KL

Katanin-like

LDH

Lactate dehydrogenase

LLPS

Liquid-liquid phase separation

LTP

Long-term enhancement

MAPs

Microtubule-associated proteins

MARKs

Microtubule affinity-regulating kinases

MBD

Microtubule-binding domain

MTBD

Microtubule-binding domain

NCLK

Neuronal cdc2-like protein kinase

NFTS

Neurofibrillary tangles

NMR

Nuclear magnetic resonance

NMDA

N-methyl-D-aspartate

NMNAT

Nicotinamide mononucleotide adenylyltransferase

NPC

Nuclear pore complex

PHF

Paired helical filaments

PTEN

Phosphatase and tensin homolog deleted on chromosome ten

rDNA

Ribosomal DNA

RBPs

RNA-binding proteins

ROS

Reactive oxygen species

SARDH

Sarcosine dehydrogenase

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SPs

Senile plaques

ThT

Thioflavin T

TIP5

Termination factor I-interacting protein 5

Xia-ping He and Yang Lu contributed equally with all other contributors.

1 Introduction

Human genetic information inside a cell encodes not only the specific structures and functions of proteins but also the way these structures are attained through the process known as protein folding (Stefani and Dobson 2003). Only in this way the nascent peptides fold into the specific conformational proteins and possess their natural biological functions. However, protein misfolding and deposition could occur, especially under endoplasmic reticulum stress and by abnormal modifications (Evans et al. 2016). The misfolded proteins are often prone to aggregation and/or interact with other cellular components causing impairment of cell viability and eventually cell dysfunction and death (Cohen 1999).

Protein aggregation plays a central role in pathological progression of neurodegenerative diseases. β-Amyloid (Aβ) deposition and Tau aggregation are major pathological hallmarks for Alzheimer’s disease (AD) (Hardy and Selkoe 2002). β-Amyloid deposition in the brain occurs in the early stage of preclinical phase, followed by neuronal Tau hyperphosphorylation and paired helical filament (PHF) formation (Jack Jr. et al. 2010). Tau protein is a member of microtubule-associated proteins (MAPs), promoting microtubule assembly and stabilizing microtubules (Goedert et al. 1989a, b, 1992; Goedert and Jakes 1990). This protein is a major constituent of PHF found in the brain of Alzheimer’s patients (Wischik et al. 1988). Native Tau is prone to hydrolysis by proteases because it lacks secondary structures and its proteolytic sites exist on the exterior surface of protein molecule in solution (Schweers et al. 1994). So far, however, what triggers protein abnormal modification, aggregation, accumulation and spreading during neurodegeneration (Franzmeier et al. 2024) or what occurs ahead of Aβ deposition and Tau hyperphosphorylation acting as an etiological factor is still unclear, though some polyanions such as heparin and polyglutamate were found to induce the Tau filament formation years ago (Friedhoff et al. 1998). To clarify this major issue is beneficial and imperative to understand the early onset and progression of age-related cognitive impairment.

Since it was first introduced as a fixative reagent in 1893, formaldehyde has still been employed for tissue preservation, including fresh-retaining purpose (Fox et al. 1985; Puchtler and Meloan 1985). Formaldehyde is widely employed in paraffin-embedded cells and tissues and also active in the reaction with proteins as a chemical cross-linker (Carpenter 1946; Hopwood et al. 1988). Theis and Lams investigated different reactive conditions to enhance the efficacy of formaldehyde to react with collagen from wool (Theis 1944). Recently, Magdeldin and Yamamoto showed their useful viewpoints to decipher proteomes of formalin-fixed paraffin-embedded (FFPE) tissues (2012). However, instead of tissue fixation and preservation, the effect of formaldehyde at low concentrations on protein aggregation and neurotoxicity needs to be investigated.

In the chemical modification of protein with formaldehyde, the α−/ε-amino groups of protein react with formaldehyde (Kitamoto and Maeda 1980). In addition to the reaction of the amino groups, the side chain groups of amino acids are also known to be involved in the reaction with formaldehyde (French and Edsall 1945). After reacting with a small amount of excess formaldehyde, His, Trp, Asn, Tyr, Phe, and Cys can form stable products, and the product structures are proposed based on classical methods (French and Edsall 1945; Kitamoto and Maeda 1980). Under the physiological conditions, however, α-/ε-amino group of protein is most sensitive to formaldehyde reaction. The reaction of formaldehyde with Tau protein may be considered to block the positive charges of Lys residues, inducing conformational changes of Tau. Lu et al. have studied the structural characterization of formaldehyde-induced cross-links between amino acids and deoxynucleosides and their oligomers. The clarified structures will provide a basis for the investigation of the characteristics and properties of DNA-protein cross-links (DPCs) formed in vivo and will be helpful in identifying biomarkers for the evaluation of formaldehyde exposure both at the site of contact and at distant sites (Lu et al. 2010). In this chapter, we discuss Tau function and dysfunction as well as its aggregation and cytotoxicity in the presence of formaldehyde.

2 Multiple Functions of Tau Protein

2.1 One of the Microtubule-Associated Members

In 1975, Weingarten et al. found a heat-stable protein essential for microtubule assembly and designated it Tau (Weingarten et al. 1975). Neuronal Tau is mainly distributed in the axonal compartment (Dehmelt and Halpain 2005) and acts in promoting and stabilizing the microtubule system involved in cellular transport and neuronal morphogenesis (Cleveland et al. 1977; Goedert et al. 1989a, b). Qiang et al. proposed new insights with respect to the claim that Tau acts on the microtubule system. They found that Tau protein is mainly found in unstable regions of axon microtubules, which can be lengthened to facilitate microtubule assembly (Qiang et al. 2018). On the other hand, the true way Tau promotes axon microtubule stability is by allowing microtubules to have unstable regions while limiting true stabilizers (other MAPs, such as MAP6) to bind to them. Therefore, they believe that Tau, although involved in microtubule assembly, is not a true axon microtubule stabilizer (Qiang et al. 2018). The structure of Tau molecule can be subdivided into an amino-terminal proline-rich domain (PRD) that projects from the microtubule surface and a carboxy-terminal MBD. To investigate microtubule binding core of the wild-type Tau protein, Nadia et al. used solid-state nuclear magnetic resonance (NMR) and found that residues 369–399 domain bind both stabilized and unstable microtubules with the highest affinity (El Mammeri et al. 2022). Incubation of bacterially expressed human Tau with sulfated glycosaminoglycans leads to bulk assembly of Tau filaments (Goedert et al. 1996), making it possible to obtain structural information (Berriman et al. 2003). Tau lacks secondary structures and is considered to exist as a “wormlike” conformation with a high flexibility in solution (Schweers et al. 1994). Therefore, the side chains of amino acid residues such as Lys, Cys, Thr, and Ser are mostly exposed and vulnerable to chemical modifications. This is why Tau protein is sensitive to phosphorylation and dephosphorylation (see Chap. 10) as well as modification by formaldehyde.

Stabilization of microtubules in the presence of Tau proteins is involved in the mitotic spindle and avoid mis-segregation of chromosomes, thereby protecting the genome (Austin et al. 2008; Rossi et al. 2008). According to Haruka Sudo, deficiency of Tau can enhance microtubule hyperacetylation by activating protein katanin-like (KL)1, and disrupt spindle microtubules (Sudo 2018). Julbert Caneus et al. found that mutant Tau (MAPT) causes mitotic spindle abnormalities, chromosome mis-segregation, and aneuploidy, which further lead to neuron and glia cells apoptosis and frontotemporal lobar degeneration (Caneus et al. 2018).

2.2 As a Role of Chaperone

Chen et al. have observed the interaction between human neuronal Tau-40 (hTau-40) and rabbit muscle D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12). As described, Tau protein did not influence the activity of GAPDH at room temperature or in solution in the absence of denaturant guanidine hydrochloride (GdnHCl) (Chen et al. 2000). Inactivation of GAPDH incubated with Tau was more distinguishably detected than that of control GAPDH during thermal and GdnHCl denaturation. Their work revealed that Tau binds to the denatured GAPDH but not the native enzyme under the experimental conditions. However, Tau suppressed refolding and reactivation of GAPDH when this enzyme was reactivated by dilution of GdnHCl solution. Tau protein could enhance the aggregation of the nonnative GAPDH in solutions, suggesting an anti-chaperone-like manner of Tau toward GAPDH in vitro, according to the definition for a protein to be regarded as a chaperone by Ellis (1990). For an anti-chaperone, just one characterization is different from the chaperone: it functions to obstruct the correct noncovalent assembly of polypeptide. Tau did not influence the activity of the native GAPDH but bound to the denatured enzyme and obstructed its reactivation. The delayed addition of Tau affecting the reactivation of the denatured GAPDH indicates that Tau does not interact with native GAPDH as a component of the assembled structure of the enzyme. This is why they regard Tau as a new anti-chaperone (Chen et al. 2000). However, Tau was inactivated in its anti-chaperone-like function when it was aggregated or phosphorylated by neuronal cdc2-like protein kinase (NCLK).

Furthermore, neuronal Tau showed chaperone-like function to lactate dehydrogenase (LDH, EC1.1.1.27) as described by Tian et al. Tau protein remarkably enhances reactivation of glutamic dehydrogenase (GDH, EC 1.4.1.3), another carbohydrate metabolic enzyme, and also shows a chaperone-like manner (Tian et al. 2004). Similar results were described by Fukuhara et al. They showed chaperone-like and anti-chaperone-like activities of amyloid fibrils of peptides from αA-crystallin (Fukuhara et al. 2012). These data indicated that either chaperone like- or anti-chaperone like-function of Tau depends on the types of substrate protein. On the other hand, recently, abundant research work has been performed on chaperones’ disaggregating Tau polymerization such as heat shock proteins (Moll et al. 2022; Zhang et al. 2022) and some ubiquitin-associated enzymes (Nadel et al. 2023). Nicotinamide mononucleotide adenylyltransferase (NMNAT, an NAD⁺ synthase) acts as a chaperone on pTau and prevents its amyloid aggregation in vitro, and mitigates its pathology in a fly tauopathy model (Ma et al. 2020).

2.3 Binding to Actin

Tau protein interacts with actin in addition to microtubules (Correas et al. 1990; Sobue et al. 1985) and is involved in the organization of the cytoskeletal network (Henriquez et al. 1995). Actin monomers (G-actin) were found to form gel-like bundles in the presence of Tau (Yamauchi and Purich 1993). According to Farias et al. (2002), G-actin inhibits the association of purified Tau with tubulin immobilized on a solid-phase support system (Moraga et al. 1993). A stronger inhibition can be observed with preassembled actin filaments. And vice versa, tubulin and its’ polymers inhibit Tau–actin interactions, indicating the competitive relationship between actin and tubulin binding to Tau. The microtubule-associated protein Tau is able to interact with actin and serves as a cross-linker between the microtubule and actin networks (Knowles et al. 1994; Kotani et al. 1985).

The cross-talk between microtubules and actin is essential for cellular functions. However, actin and tubulin cannot directly link together without cross-linking proteins. In the absence of MAPs, F-actin and microtubules cannot interact (Doki et al. 2020). The Microtubule-binding domain (MTBD) of Tau protein is involved in its interaction with actin. To address the function of other domains of Tau in this interaction, Hai-Jin He et al. constructed several tau truncation and deletion mutants (Table 8.1). The proline-rich domain truncation mutant (tauPRD), the microtubule-binding domain (tauMTBD), and the microtubule-binding domain deletion mutant (tauΔMTBD) are able to promote the formation of actin filaments (F-actin). Native Tau was used as positive controls (He et al. 2009). However, actin assembly could not be observed in the presence of the N-terminal or C-terminal truncation mutant. In other words, the PRD is involved in the association of Tau with G-actin. Further studies with co- sedimentation and electron microscopy (EM) demonstrated that the PRD is also capable of binding to F-actin and inducing the formation of F-actin bundles. Using solid-phase assays to analyze apparent dissociation constants for the interaction of Tau or its mutants with F-actin resulted in a sequence of affinity for F-actin: native Tau>MTBD>PRD. Based on these data, we can see that Tau protein binds to and induces bundling F-actin through its PRD and MTBD.

Table 8.1

Roles of MTBD and PRD of Tau protein

Microtubule

Actin

DNA/RNA

tauN

N-terminal region

−

−

−

tauPRD

Proline-rich domain

+

+

+

tauMTBD

Microtubule binding domain

++

++

++

tauΔMTBD

C-terminal region truncation mutants

+

+

+

tauC

Microtubule binding domain

−

−

−

Native Tau

Proline-rich domain/microtubule binding domain deletion mutants

+++

+++

+++

Tau protein interacts with tubulin, actin, DNA, and RNA through its MTBD and PRD (He et al. 2009; Wei et al. 2008)

To reveal how Tau regulates F-actin polymerization and structure, Cabrales et al. explored information on Tau binding sites on F-actin. First, several actin-binding proteins were able to bind to the hydrophobic pocket between G-actin subdomains 1 and 3, and cryo-EM. Studies showed that the site of F-actin binding by one of the binding partners, cofilin, was highly consistent with that of G-actin. Afterward, cofilin was used to validate the binding site of Tau to F-actin. They observed that Tau was no longer bound to F-actin after the addition of an excess of cofilin. Co-precipitation experiments also showed the co-precipitation of Tau with F-actin reducing in the presence of cofilin (Cabrales Fontela et al. 2017). Subsequent studies of the effect of paramagnetic centers on NMR resonances further supported the binding site of Tau at actin on the hydrophobic pocket between actin subdomains 1 and 3. However, the affinity for F-actin will diminish and cannot bundle actin filaments when Tau is phosphorylated by microtubule-associated protein/microtubule affinity-regulating kinases (MARKs) 2 (Cabrales Fontela et al. 2017).

In order to clarify the mechanisms underlying the microtubule-actin organization by cross-linkers, Elie et al. exhibited that neuronal Tau binds to actin and microtubules simultaneously, promoting in vitro co-organization and coupled growth of both networks. Tau protein is able to induce the guided polymerization of actin filaments along microtubule tracks and growth of single microtubule along actin filament bundles (Elie et al. 2015). They revealed that at least two of the four Tau-repeated motifs, primarily identified as tubulin-binding sites, are required to associate the two cytoskeleton microtubules and actin. Tau, acting as a linker, enables a coordination of the microtubule and actin networks that might be essential in various neuronal contexts for cellular skeletons. As described by Cabrales et al., the interaction of Tau with actin affects synaptic plasticity, and in particular, binding to F-actin is involved in dendritic spine morphology and postsynaptic reorganization (Cabrales Fontela et al. 2017). In addition, to investigate the up-stream risk factors to induce Tau protein aggregation, Tsujikawa et al. revealed that actin-binding protein filamin-A drives Tau aggregation and contributes to progressive supranuclear palsy pathology (Tsujikawa et al. 2022).

2.4 DNA-Tauosome

Tau has a higher affinity for DNA than for microtubules (Corces et al. 1980) and is found in the nuclei of several cell lines such as human neuroblastoma cells (SH-SY5Y), mouse neuro-2a (N2a) cell line, human macrophages, monkey kidney cells, and PC12 cells (Brady et al. 1995; Cross et al. 2000; Loomis et al. 1990; Thurston et al. 1996; Wang et al. 1993). The distribution of Tau in the nucleus is thought to enable condition- and subcellular environment-dependent interactions (Sotiropoulos et al. 2017). All six isoforms of Tau have been observed to bind to nucleolar organizer regions of acrocentric chromosomes and the fibrillar region of the nucleoli (the site for rRNA transcription) in some non-neuronal cells, for instance, lymphocyte (Thurston et al. 1996). Greenwood et al. isolated nuclei and observed that Tau was covalently cross-linked to DNA, representing the binding of Tau to DNA in the nucleus (Greenwood and Johnson 1995). Sjoberg et al. proposed a functional role for nuclear Tau in relation to nucleolar organization and heterochromatinization of a portion of RNA genes (Sjoberg et al. 2006).

2.4.1 Protecting Double-Stranded DNA

In 2003, Hua and He proposed a hypothesis: Tau could protect DNA double helix structure (Hua and He 2003). The hypothesis is based on the following observations: (1) Tau enhances the melting temperature of calfthymus DNA, showing that Tau is able to stabilize the DNA double helix during thermal conditions (Hua and He 2000). (2) Tau will accelerate the refold of thermally denatured DNA when the temperature decreases (Hua et al. 2003). (3) Ma et al. employed the phen-copper complex as a model to study the effect of Tau on the oxidative DNA damage (Ma et al. 1998). Tau could not directly scavenge ROS but prevent DNA from ROS attacks in vitro, because the background light emission was observably caused by ROS. (4) Sultan et al. proposed that nuclear Tau is a key player in DNA protection. They showed Tau-mediated DNA protection in postmitotic neurons and proposed a scheme illustrating the nuclear Tau protection of DNA integrity in heat-stressed neurons (Sultan et al. 2011). These data demonstrate the protective effect of Tau protein on DNA. In 2014, Lu et al. demonstrated Tau isomers also localized in the nucleus of neurons by immunohistochemical staining and gene knockout (Lu et al. 2014).

Mounting evidence suggests that DNA damage plays a central role in aging (Petr et al. 2020). Accumulation of nuclear Tau increases during aging, which may relate to its described role in activating transposons and subsequently accelerating aging (Anton-Fernandez et al. 2023). Recently, the relationship between Tau and DNA damage was emphasized in neurodegeneration (Colnaghi et al. 2020). Tau’s interaction with the DNA to protect the genome mainly when dephosphorylated supports the viewpoint that aberrant modifications including phosphorylation and nonenzymatic glycation in diseases like AD alter its function and enhance genome vulnerability and neurodegeneration (Maina et al. 2018; Yekta et al. 2022). It was found that Tau preferentially binds to adenine and guanine-rich sequences in DNA (Benhelli-Mokrani et al. 2018). Tau interacts with DNA and RNA, maintains their integrity, and protects them from oxidative damage (Colnaghi et al. 2020; Lester and Parker 2024). Postmitotic neurons accumulate DNA damage during decades of brain aging. Requejo-Aguilar offered a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to neurodegeneration by cell cycle activation, especially Tau phosphorylation and DNA damage response (Requejo-Aguilar 2023). Nuclear Tau expression protects genomic DNA and stabilizes the peripheral and nucleolar heterochromatin blocks in the senile neuron (Alonso et al. 2024). Diez and Wegmann (2020) considered nuclear transport deficits playing important role in Tau-related neurodegenerative diseases. As Yekta et al. consider, the protein flexibility is important for Tau binding to DNA. They used surface plasmon resonance and confirmed that the glycation leads to the conformational rigidity of Tau and remarkably reduces the binding affinity of Tau protein to DNA (Yekta et al. 2022). Prefibrillar Tau oligomers were found to alter the nucleic acid protective function of Tau in hippocampal neurons in vivo (Violet et al. 2015). In addition, Tau was inactivated in its binding to DNA, when Tau was induced by formaldehyde to aggregate (Hua and He 2002). That is to say, how to maintain Tau protein modified under physiological conditions and maintain its correct functional conformation will be a strategy for the protection of DNA structure and function.

As described by Krylova et al., Tau protein is capable of binding to single-stranded DNA with sequence specificity. They tried to demonstrate their viewpoint using an in vitro method with nonequilibrium capillary electrophoresis of equilibrium mixtures. Tau protein bound to one of double-stranded DNA in a sequence-specific fashion, which could induce dissociation of strands in dsDNA (Krylova et al. 2005). So far, however, the biological function of Tau protein associated with single-stranded DNA is still under investigation.

2.4.2 DNA-Tauosome Complex

The complex of Tau associated with DNA features in a “beads-on-string” structure under EM. Association of Tau bends double-stranded DNA into a globular-like complex (Hua et al. 2003). Observing using atomic-force microscope (AFM), Qu et al. showed that the complex of Tau protein associated with double-stranded DNA looks like histone-DNA complex (Camero et al. 2014; Qu et al. 2004). Interacting with native Tau, DNA converted to a folded globular structure (average diameter, 27.42 ± 0.73 nm) (Lu et al. 2013). However, bovine serum albumin (BSA) as a control did not show the same effect on double-stranded DNA.

As described by Wei et al., Tau protein binds to the minor groove of DNA helix structure (Fig. 8.1). This viewpoint is supported by these observations: (1) Tau could be displaced from double-stranded DNA in the presence of the minor groove binders, for instance, distamycin A (Wei et al. 2008). (2) Tau is able to prevent DNA from degradation by DNase I, which also recognizes the minor groove of the double strands (Wei et al. 2008). (3) Histones associated with the minor groove without nucleotide sequence specificity are also able to replace Tau from DNA helix (Hua et al. 2003; Qu et al. 2004). (4) Methyl green, a major groove binder (Kumar and Muniyappa 1992; Simonsson et al. 1998; Tuite et al. 1997), cannot displace Tau from association with DNA. Finally, (5) Tau protein would associate with DNA in a sequence-specific manner if it is bound to the major groove (Alberts et al. 2002; Roy 1996). All these results point out that Tau protein acts as a minor groove binder to the double-stranded DNA (Hua et al. 2003; Lu et al. 2013; Wei et al. 2008).

Fig. 8.1

A hypothetic model of DNA-Tauosome. The complexes of DNA chain and Tau protein under electron microscopy (panel a). The proline-rich domain and the microtubule-binding domain may bind to the DNA minor groove in the same orientation plane, leading to fold the DNA helix. A putative morphology of DNA-Tauosome in a painted diagram (panel c) (He 2017)

As mentioned above, Tau contains proline-rich domain and (MBD) besides N-terminal and C-terminal region (He et al. 2009; Holt and Koffer 2001; Lee et al. 1989). In author’s opinion, both PRD and MTBD may associate simultaneously with the minor groove of double-stranded DNA, approximately within the same plane, though the calibration of the plane needs to be investigated (Wei et al. 2008). This hypothetical binding model is based on the following data: (1) Tau binds stably to a 13-bp or longer polynucleotides. In the case of a 10-bp polynucleotide, the DNA helix is not long enough to provide its minor groove for both PRD and MTBD to bind in the same orientation plane at the same time. (2) DNA chain could bend when protein binds helix in the same orientation plane (Ukiyama et al. 2001). In this case, the association of Tau definitely bends the double-stranded DNA. (3) In contrast, the DNA strands would not be bent if the two domains bound to the helix in different orientations. Finally, (4) as result from the binding in the same orientation, DNA chain could surround the surface of Tau protein like DNA helix surrounds the histone octamer complex if several Tau molecules are associated with bent DNA. This may be a putative mechanism for the formation of DNA-Tauosome from Tau and DNA. Of course, whether DNA-Tauosome exists in vivo still needs further investigation.

2.4.3 Suppression of DNA Amplification

What is the putative function of the interactions between Tau and DNA? To investigate DNA’s effect on Tau, Tetz et al. evaluated the effect of DNA extracted from a variety of prokaryotic and eukaryotic cells in Tau misfolding and aggregation. They found DNA of bacteria, especially those previously detected in the brain, cerebrospinal fluid, or oral cavity of patients with AD results in a more pronounced Tau misfolding compared to eukaryotic DNA, somehow indicating a bacterial infection and AD (Tetz et al. 2020). To clarify the effect of Tau on DNA, Li et al. used both polymerase chain reaction (PCR) and real-time PCR in the experiments. As described by Li et al. (2005), Tau protein is able to repress DNA amplification. A strong repression could be observed when an in vitro DNA replication assay was performed at the physiological temperature (37 °C). The incorporation of dNTP was markedly decreased to approximately 12 or 15% in the presence of Tau23 or Tau40 compared with BSA as a control group. In the competitive experiments, the PCR product could be restored when the competitor DNA was added (Li et al. 2005). This is to say, the association of Tau with the template gives rise to the repression.

The repression on DNA replication appears that Tau could play a role in gene silence because Tau isomers localized in both cytoplasm and nucleus (Lu et al. 2014). As we know, the function of Tau is regulated by phosphorylation and dephosphorylation. Tau could dissociate from DNA when it is phosphorylated (Lu et al. 2013). The other modifications also affect Tau’s function such as glycosylation (Wang et al. 1996), hydroxymethylation/methylation by formaldehyde (He et al. 2010; Magdeldin and Yamamoto 2012), and acetylation (Cook et al. 2014). Glycosylation appears to be responsible for the maintenance of the PHF structure, although the abnormal phosphorylation might promote aggregation of Tau and inhibition of the assembly of microtubules (Wang et al. 1996). Modification by formaldehyde also impedes Tau binding to DNA, leading to inactivation of Tau protein to suppress DNA replication. Transcription termination factor I-interacting protein 5 (TIP5) is a protein that stabilizes heterochromatin and inhibits ribosomal DNA (rDNA) transcription, and Maina et al. detected co-localization of Tau with TIP5 in the nucleolus, indicating that Tau is involved in regulating rDNA silencing (Maina et al. 2018).

2.5 Binding to RNA and Regulating RNA Metabolism

In 1975, the interaction of protein Tau with RNA was investigated by Bryan et al., who proposed that protein Tau bound to RNA and the association inhibited microtubule assembly (Bryan et al. 1975). Later, RNA was found to stimulate aggregation of protein Tau into Alzheimer-like PHFs (Hasegawa et al. 1997; Kampers et al. 1996). Using cytoplasmic acridine orange (AO) histo-fluorescence, Ginsberg et al.demonstrated that the fluorescence signal abolished with RNase, but not DNase or proteinase K, indicating the relative specificity of AO for RNA species. Their observations demonstrated the presence of RNAs in neurofibrillary tangles (NFTs) and senile plaques (SPs) (Ginsberg et al. 1997). According to Zhang et al., RNA stores Tau protein reversibly in complex coacervates, suggesting that the droplet state can incubate Tau and predispose the protein toward the formation of insoluble fibrils (Zhang et al. 2017).

Tau protein contains two major domains (Kanai et al. 1992), a projection domain (Hirokawa et al. 1988) and MTBD (Lee et al. 1989). The projection domain is composed of an acidic and a proline-rich region. As mentioned above, Tau interacts with actin and DNA via the PRD and MTBD. Kampers et al. prepared 21 mutants of Tau protein to investigate which domain is involved in the RNA-induced assembly of PHFs (Kampers et al. 1996). The MTBD plays a role in the interaction between Tau and RNA. The three-repeat constructs polymerize most efficiently, and two-repeat constructs are the minimum number required for assembly. Wang et al. investigated the interaction of Tau with RNA via both the MTBD and PRD. Using gel-retardation assay and atomic-force microscopy (AFM), they found that Tau binds to tRNA, rRNA, and mRNA in nonsequence specificity. Tau was observed to bind to both the double-stranded RNA (polyA₁₅/U₁₅) and the single-stranded RNA (polyA₃₀) when Tau was incubated with the synthetic polynucleotides (Wang et al. 2006). In the analysis of the net charge distribution of Tau, five mutants were constructed such as the fragments of the N-terminal region, the proline-rich domain, the microtubule-binding domain, and the C-terminal region (Table 8.1). Electrophoretic mobility shift assay (EMSA) showed that PRD and MTBD are involved in the association with RNA, but N-terminal region and the C-terminal region are not. The association of Tau with RNA is observably disturbed in acidic solutions (pH < 5) or in the presence of NaCl (>0.5 M). In other words, the electrostatic interaction is mainly involved in the binding of Tau to RNA. The results from indirect immunofluorescence assay indicate that Tau protein and RNAs are partially co-localized both in cytoplasm and nucleoplasm in SH-SY5Y cells. These data suggest that Tau probably interacts with RNA in vivo under physiological state. In addition, Tau can interact with nucleoporins of the nuclear pore complex (NPC) that control the transport of proteins and RNA into and out of the nucleus, and affect the integrity of RNA in the cytoplasm and nucleus, which can regulate RNA metabolism when cells are under stress, thereby protecting RNA from degradation (Eftekharzadeh et al. 2018).

However, Li et al. investigated whether Tau could affect RNA transcription in vitro. As shown in their results, Tau did not repress the yield of RNA in transcription although the protein binds to DNA in nonspecific manner. It appears that Tau could be replaced or ejected from the template by the elongating T7 RNA polymerase (Li et al. 2005). Guo et al. used a Drosophila adult nervous system relevant to AD to find transposable elements’ transcriptional activity in some Tau transgenic fly adults are significantly increased. But the effects are variable depending on the Tau genotype (wild-type versus mutant), aging, and the specific element examined (Guo et al. 2018). And Baquero et al. found that Tau can bind different RNA-binding proteins (RBPs) to regulate mRNA processing and participate in RNA metabolism (Baquero et al. 2019).

As described by Wang et al., binding to RNA results in protein Tau aggregation and induces the formation of PHF-Tau in SH-SY5Y cells (Wang et al. 2006). Besides soluble globule-like state and solid-like aggregates, proteins have been observed to undergo liquid–liquid phase separation (LLPS) in vivo and in vitro (Lin et al. 2023). The authors established a method to mapping phase diagram of Tau-RNA LLPS (Tau-RNA complex coacervation system) under live cell co-culturing conditions. Binding of RNA also induces Tau aggregation in LLPS, according to Zwierzchowski-Zarate et al. (2022). They have tested whether RNA exerts sequence-specific effects on Tau assembly and strain formation. Although polyA-, polyU-, and polyC-RNA all bound to protein Tau, only polyA-RNA triggered seed and fibril formation, suggesting that human RNA specifically induces formation of stable Tau strains and may trigger the formation of dominant pathological assemblies. The RNA-induced Tau fibrils were dissolved when RNase was added, showing that RNA is necessary for fibril integrity (Zwierzchowski-Zarate et al. 2022). To prevent Tau-RNA aggregation, Venkatramani et al. employed a natural naphthoquinone, shikonin to impede the oligomerization and fibrillization of Tau. RNA-induced Tau aggregation was strongly inhibited by the compound (Venkatramani et al. 2022).

2.6 Regulation of Brain-Insulin Signaling

Tau protein was not only present in the brain but has also been found to be abundantly present in pancreatic β-cells (Martinez-Valbuena et al. 2019). Insulin was co-localized with Tau protein in islets of wild-type mice and humans (Benderradji et al. 2022). Studies in rodents demonstrated that brain insulin regulates metabolism and neural behavior (Soto et al. 2019). Brain-insulin signaling mediates synaptic plasticity and memory formation, and is essential for maintaining peripheral energy homeostasis (Leboucher et al. 2019; Rhea et al. 2024). Marciniak et al. have found the ability of Tau to manipulate hippocampal responses to insulin in the brain, illustrating that Tau itself maintains metabolism and energy homeostasis by participating in regulation of brain-insulin signaling (Marciniak et al. 2017). The cytoskeleton (actin and microtubules) contributes to the movement of insulin (Thurmond et al. 2003). The actin cytoskeleton and F-actin could promote the movement of insulin vesicles to the plasma membrane to stimulate insulin release (Varadi et al. 2005). Disassembly of cortical F-actin also enhances insulin secretion (Thurmond et al. 2003).

In 2020, Benderradji et al. found that loss of Tau function (knockdown, Knockout or knock-in) impairs glucose-stimulated insulin secretory function (GSIS) (Benderradji et al. 2022). Goncalves et al. also found that Tau knockout mice develop hyperglycemia and glucose intolerance at an early age (2 months) and insulin resistance at 7 months (Goncalves et al. 2020). As described by Marciniak et al., insulin regulation by neuronal Tau was not limited to the hippocampus and may involve multiple brain regions, and the metabolic changes observed in Tau KO mice may be due to the inability of the hypothalamus to respond appropriately to insulin (Marciniak et al. 2017). When insulin signaling was impaired, it accelerates Tau hyperphosphorylation and aggregation (Gratuze et al. 2018). Similar results have been described by Yarchoan et al. who reported the development of cerebral insulin resistance in the postmortem brain of patients with tauopathy (Yarchoan et al. 2014).

To clarify the mechanism by which Tau regulates brain-insulin signaling, Marciniak et al. expressed human neuronal Tau (hTau) in WT mice and N1E-115 cells. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) was a phosphatase homolog to the tension protein that inhibits the transduction of insulin signaling. They found Tau protein co-immunoprecipitated with PTEN in mouse brain tissue and N1E-115 cells; they therefore speculated that there was an interaction between Tau and PTEN. They found that Tau impaired the lipid phosphatase activity of recombinant PTEN by decreasing the dephosphorylation of PtdIns (3,4,5) P3. Further studies of cellulose bioluminescence resonance energy transfer (BRET) experiment showed that the expression of tau protein not only promoted the formation of PtdIns (3,4,5) P3, but also enhanced the activity of PtdIns (3,4,5) P3 through regulating insulin (Marciniak et al. 2017). Ho et al. then confirmed by Tau knockout mice that another function of Tau was to regulate the transport of insulin vesicles through microtubules between inside and outside the cell to maintain normal insulin secretion; in addition they showed that increased microtubule dynamics is due to enhanced glucose metabolism (Ho et al. 2020). Based on these studies, we can speculate that the interaction between Tau protein and PTEN inhibits PTEN’s phospholipase activity and facilitates brain-insulin signaling. Tau acts as an active modulator of microtubules to regulate insulin secretion involved in the regulation of brain-insulin signaling. On the other hand, Tau may function in insulin sensitivity, and loss of its function by aggregation and deletion could result in insulin resistance (Al-Lahham and Mendez 2023). Brain insulin resistance may be one of multiple causes of Tau hyperphosphorylation, Medina-Vera et al. (2024) considered inositol as an insulin sensitizer and candidate for drug development.

3 Formaldehyde Induces Tau Aggregation and Dysfunction

3.1 Tau Aggregation in the Presence of Formaldehyde

In author’s laboratory, aggregation of Tau protein was observed in the presence of ethanol with disuccinimidyl suberate (DSS), a chemical cross-linking agent (He et al. 1998). Formation of Tau polymers by fluorescence (λem = 333 nm; λex = 280 nm) was observed when the proteins were aggregated in solutions (Luo and He 1999; Luo et al. 2000a). Tau aggregation was also investigated by applying thermal conditions and denaturant of guanidine HCl (Luo et al. 2000b). As described previously, Tau was markedly aggregated when treated with aldehydes including acetaldehyde, glutaraldehyde, and formaldehyde at different concentrations (Hua et al. 2002; Luo and He 1999). The effect of aldehyde on the phosphorylation of Tau protein with NCLK (Chen et al. 1999), which is one of the kinases promoting Tau hyperphosphorylation in the brain of Alzheimer’s patients, was also observed (Paudel 1997a).

Yu and his group studied the function of semicarbazide-sensitive amine oxidase (SSAO) and considered that the formation of formaldehyde from adrenaline is a potential risk factor for stress-related angiopathy (Yu 1990; Yu et al. 1997). He proposed a hypothesis that SSAO-associated aldehydes, such as formaldehyde and methylglyoxal, could be crucially important in the pathogenesis of vascular dementia, AD, and diabetic complications (Yu 2001). Yin proposed that the formation of “carbonyl protein” is related to the process of aging (Yin 1992). Treatment with formaldehyde not only induced Tau aggregation but also inactivated its binding to DNA (Hua and He 2002). Compared with the aggregation of BSA, Tau protein was much more sensitive to the treatment of formaldehyde. Further experiments show that the intensity of light scattering of neuronal Tau-40 solution at 480 nm increased markedly in the presence of low concentrations of formaldehyde. 8-Anilino-1-naphthalenesulfonic acid (ANS) binding assay showed that a putative hydrophobic core is formed in Tau polymers during incubation with formaldehyde (Nie et al. 2005). Native Tau was rapidly hydrolyzed by immobilized earthworm fibrinolytic enzyme II (EFE II), producing a digested fragment (36–37 kDa). However, formaldehyde-treated Tau was not so easy to be digested under the same experimental conditions. The aggregated Tau forms a hydrophobic core and becomes relatively rigid in its polymers. These results suggest that neuronal Tau is one of the target proteins for formaldehyde which may be related to neurodegeneration.

Further study in the summer of 2006 by Nie et al. showed that low concentrations of formaldehyde induced human Tau protein to form neurotoxic aggregation. Their data supported that formaldehyde played a role in the induction of Tauopathies in age-related cognitive impairment (Nie et al. 2007b). In the winter of 2006, Yu et al. incubated Aβ with formaldehyde and showed the effect of aldehydes on Aβ aggregation in vitro. Their results supported the involvement of endogenous aldehydes in amyloid deposition related to AD (Chen et al. 2007). They proposed that increased SSAO-mediated deamination may contribute to protein deposition, formation of plaques, and inflammation and thus may be involved in the pathophysiology of chronic vascular and neurological disorders, such as diabetic complications, atherosclerosis, and AD.

3.2 Tau Aggregation and Inactivation in the Presence of Formaldehyde

Native Tau is prone to misfolding and inactivation in the presence of low concentrations of formaldehyde in vitro though these protein features in a “wormlike” flexible conformation (Nie et al. 2005; Schweers et al. 1994). Abnormally modified Tau followed by aggregation plays a role in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Guo et al. 2017). As shown in Fig. 8.2, formaldehyde-treated Tau polymerizes into soluble globule-like aggregation with positive staining in both thioflavin T (ThT) and Congo red (Nie et al. 2007a). Under the same conditions, acetaldehyde-treated Tau did not markedly show protein aggregations detected by AFM. To induce Tau aggregation in the presence of acetaldehyde, it needs higher concentrations of the aldehyde and protein. Formaldehyde, unlike acetaldehyde, is not active in volatilization; hence, a precise result can be obtained in the experiment. Definitely, formaldehyde treatment induces inactivation of Tau in its binding to tubulin and stabilizing microtubule.

Fig. 8.2

Tau aggregation and cell death. Neuronal Tau was expressed and purified as described (Paudel 1997b). The purified Tau protein was loaded on the Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and analyzed by Western blotting (panel a). Tau protein (20 μM) was incubated in 50 mM phosphate buffer (pH 7.2) in the presence of 0.1% formaldehyde at 37 °C overnight (panel b). Bar = 25 nm for AFM. Tau protein was incubated in the absence of formaldehyde as control (panel c). SH-SY5Y cells were cultured in the presence of formaldehyde-treated Tau aggregation (panel d), self-aggregated Tau (panel e), native Tau (panel f), and control culture in DMEM without serum (panel g). Cells were stained by Hoechst 22258, and arrows designate the apoptotic nuclear profiles (Li et al. 2008). Bar = 25 μm for cells

3.3 Formaldehyde Treatment Inactivates Tau in the Association with DNA

Tau is a microtubule-associated protein, which is associated with its cytoplasmic localization in neuronal cells. As mentioned above, native Tau is active in association with DNA. Thus, the effect of formaldehyde on the interaction of Tau with DNA has been studied by Hua et al. They incubated Tau with formaldehyde and dialyzed the residual aldehyde. Then they employed EMSA to detect whether formaldehyde-treated Tau is still active in binding to double-stranded DNA. EMSA depicted a marked inactivation of formaldehyde-treated Tau in inter-acting with DNA. This is to say, formaldehyde treatment inactivates Tau protein in its association not only with microtubule but also with DNA (Hua and He 2002). Protein Tau is also localized at the cell nucleus in which it may be a nucleic acid-associated protein by its preferential binding to DNA sequences present in the nucleolus and pericentromeric heterochromatin (Sjoberg et al. 2006; Wei et al. 2008). An increase in the amount of nuclear Tau takes place as aging, which could be associated with the role of Tau protein in the activation of transposons and further aging acceleration (Anton-Fernandez et al. 2023).

Formaldehyde reacts with α-/ε-amino groups of a protein (Nie et al. 2007a, b), which suppresses Tau protein in the association with DNA. In other words, lysinyl residues are the essential residue for Tau to interact with DNA. The author and collaborators constructed the mutants of tauN and tauC and then incubated them with DNA, respectively. The association of the two mutants with DNA could not be observed on EMSA. This indicates that the Lys residues out of the PRD and MTBD may not be the main contributors to the DNA binding (Wei et al. 2008).

The lysinyl residues in the PRD and MTBD are essential to interact with the minor groove of DNA helix. The PRD (7 Lys) and MTBD (12 Lys) contains 19 lysinyl residues in total, and some of them are supposed to be involved in the interaction between Tau and DNA. This viewpoint is based on the following points: (1) the pK of the ε-amino group of lysinyl residue is 10.8 when interacting with DNA bases in electrostatics; (2) the interaction between Tau and DNA is markedly suppressed at the pH higher than 12, showing the interaction is electrostatic dependent as measured by EMSA; and (3) addition of formaldehyde significantly interferes with the association of Tau with DNA (Wei et al. 2008). Note that since formaldehyde induces Tau aggregation, DNA-Tauosome could not be observed after the protein is treated with the aldehyde.

4 Formaldehyde-Treated Tau Becomes Cytotoxic

4.1 Formaldehyde-Treated Tau Features in Globular-like Aggregation with Cytotoxicity

As described previously (Nie et al. 2007b), unlike the typical globular protein BSA, the natively unfolded structure of human neuronal Tau was induced to misfold and aggregate in the presence of low concentrations of formaldehyde, leading to the formation of globular-like deposits that appeared as densely staining granules under electron and AFM and bound the amyloid-specific dyes thioflavin T and Congo red. This suggests that formaldehyde-treated Tau may feature in amyloid-like aggregation. Amyloidosis disease is caused by accumulation of proteins in the form of abnormal, insoluble fibers, known as amyloid fibrils (Pepys 2006). As kinetic study shows, Tau can rapidly polymerize in 60 min in 0.1% formaldehyde solution. SDS-PAGE results also exhibit Tau polymerization in the presence of formaldehyde. However, neuronal Tau misfolds and aggregates into globular-like polymers in formaldehyde solutions. No fibril-like polymerization could be observed, while Tau protein was incubated with formaldehyde for 15 days apart from globular-like aggregation observed by AFM and EM. This suggests that formaldehyde polymerization is involved in Tau aggregation. Such aggregation process is probably linked to the Tau’s special “wormlike” conformation, which leaves the ε-amino groups of lysinyl residues and thiol groups of Cys residues exposed to the exterior. Such a structure can easily be reacted with formaldehyde in vitro and in vivo.

It is known that formaldehyde molecules are prone to polymerization. Polymerization of formaldehyde itself results in the aggregation of Tau protein. Immunocytochemistry and thioflavin S (ThS) staining of both endogenous and exogenous Tau in the presence of formaldehyde at low concentrations in the cell culture and in animal model (Nie et al. 2007a, b) have shown that formaldehyde can induce Tau into globular-like aggregates in vivo during cell death. However, formaldehyde-treated Tau showed a stronger cytotoxicity than formaldehyde-treated BSA. The significant aggregation of Tau induced by formaldehyde and the severe toxicity of the aggregated Tau to neural cells suggested that chronic toxicosis resulted from formaldehyde is related to neurodegeneration and age-related cognitive impairment (Li et al. 2008, 2016).

To demonstrate the effect of formaldehyde on cell viability, the author and collaborators removed the residual formaldehyde and used the globular-like aggregates of Tau to incubate with SH-SY5Y cells and rat hippocampal cells. Tau was shown in single protein band in SDS-PAGE (Fig. 8.2a). The formaldehyde-treated Tau is able to induce apoptosis in both neurotypic SH-SY5Y cell line (Fig. 8.2d–g) and the rat hippocampus, as observed by Hoechst 33258 staining, assay of caspase-3 activity, and flow cytometry using annexin V and propidium iodide staining. SH-SY5Y cells and rat hippocampal cells incubated with Tau aggregates, formed in the presence of acetaldehyde or in the absence of additives (and which did not show appreciable binding of ThT or Congo red), did not markedly show signs of apoptosis. Note that the concentration of formaldehyde used was not higher than 0.05 mM and depended upon the inoculation cell size. Further experiments showed that Congo red specifically attenuated the caspase-3 activity which is activated by globular-like deposits of Tau. In other words, low concentrations of formaldehyde may play a role in Tauopathies.

To further understand the globular-like aggregation, we suppose formaldehyde-induced Tau protein polymerization may features and undergoes LLPS in vitro at least. As we know, protein aggregation processes from several stages: abnormal modification, misfolding in liquid-like condensate, and solid-like condensate (Zhang et al. 2022). According to our experimental results, significant increases in the light scattering of Tau with different concentrations formaldehyde were detected, suggesting the formation of aggregation in the solution (Nie et al. 2007a). The protein aggregation becomes larger with time. When the incubation time was prolonged, the protein deposition could not be separated even in SDS-PAGE. Based on AFM observations, the globular aggregation of Tau in low concentrations of formaldehyde formed with observably clear profiles (Nie et al. 2007b). As shown in Fig. 8.2b and c, protein Tau undergoes soluble liquid-condensate and then solid-like condensate states in the presence of formaldehyde (Lin 2024).

Now that formaldehyde-induced Tau features in globular-like soluble deposits, Nie et al. investigated the effect of low concentrations of formaldehyde on protein misfolding and aggregation in cells. They incubated SH-SY5Y cells with low concentrations of formaldehyde and then probed Tau protein with Tau1 (antibody against total Tau) and protein aggregation with ThS staining. ThS-positive protein aggregation can be seen inside the cell overlapped with Tau protein in the presence of formaldehyde (Nie et al. 2007b). To confirm that the intracellular ThS-positive aggregation was Tau, the authors performed Western blotting with anti-HA-Tau in the cells. Formaldehyde is able to induce Tau into ThS-positive aggregation. That is to say, formaldehyde causes intracellular protein aggregation and deposit in cells (Nie et al. 2007b). However, whether the ThS-positive stained protein aggregation is localized in the cell or on the membrane needs further investigation.

In recent years, formaldehyde-induced protein aggregation and cognitive impairment for animals were employed as common and useful models in drug and other purposes studies. Not a few laboratories investigated drugs and employed them to reduce formaldehyde-induced cytotoxicity. Sayad-Fathi et al. used the methanolic extract of Cinnamomum zeylanicum bark to improve formaldehyde-induced neurotoxicity through reduction of phospho-Tau (Thr231), inflammation, and apoptosis (Sayad-Fathi et al. 2020). Curcumin was also found to modulate the phosphorylation of Tau, which indicated the neuroprotective potency. Dubey et al. exposure to curcumin and curcumin-Artemisinin (Cur-Art) co-amorphous restored the impaired nuclear transport in formaldehyde-stressed cells, suggesting that curcumin and Cur-Art co-amorphous exhibit therapeutic potential against Tau protein in Alzheimer’s disease (Dubey et al. 2023). Silibinin was also observed to ameliorates formaldehyde-induced cognitive impairment by inhibiting oxidative stress the experiments with in rodents (Wei et al. 2022). It is believed that there will be more drugs and agents to decrease or inhibit formaldehyde-induced cytotoxicity and neural impairment released in the future.

4.2 Formaldehyde Might Induce Tau Form Pore-Like Aggregation

Quist et al. (University of California, Santa Barbara) proposed a hypothesis of “aspecific amyloid ion channels” to explain the pathomechanism of cell dysfunction and death during neurodegenerative diseases (Quist et al. 2005). Pre-fibrillar aggregates may interact with reconstituted phospholipid membranes and with cell membrane where they form a specific-channels disrupting cellular homeostasis. The latter possible mechanism of toxicity is similar to that displayed by antimicrobial peptides, pore-forming eukaryotic proteins, bacterial toxins, and newly synthesized cyclic peptide antibiotics (Stefani and Dobson 2003).

As has been mentioned above, formaldehyde-treated Tau features in globular-like aggregation. However, amyloid-like fibrils of Tau could not be observed in the presence of formaldehyde. This is to say, formaldehyde-treated Tau exists in soluble oligomers and polymers. According to our hypothesis, “Dysmetabolism of endogenous formaldehyde may be one of the risk factors involved in sporadic age-related cognitive impairment,” the authors incubated Tau protein with formaldehyde and observed globular-like deposits with marked cytotoxicity. Under the experimental conditions, “pore-like” aggregates of Tau protein could be exhibited on the mica surface by AFM after the protein was treated with high concentrations (>0.5%) of formaldehyde. It seems to be a novel approach to study the mechanism of cellular metabolic disturbance, even cell death, which is induced by formaldehyde-treated neuronal Tau. However, the repeatability of this morphology is low in the observations. The authors did not observe the “pore-like aggregation” by EM. Therefore, whether the pore-like aggregation could be formed in water solution in the presence of formaldehyde still needs to be investigated in vivo and in vitro.

5 Cellular Formaldehyde, Abnormal Lysosome, and Protein Aggregation

Lysosomes are classically considered as systems for protein degradation (Cuervo and Dice 1998). Recent progress in fluorescent probes allows formaldehyde molecules to be detected in living cells (Brewer and Chang 2015; Descamps et al. 2010). Tang et al. incubated HeLa cells with Na-FA (a two-photon fluorescent probe) and organelle indicators such as ER-Tracker™ Red (BODIPY TR Glibenclamide), LysoTracker Red DND-99, MitoTracker Red CMXRos, and Golgi-Tracker Red (Tang et al. 2016b). Their data indicated that the probe Na-FA is located in the endoplasmic reticulum, the Golgi apparatus, and the lysosome (Xiong and Zhu 2016), but very little is present in the mitochondria. Later, they emphasized the lysosome-targeted turn-on fluorescent probe for endogenous formaldehyde in living cells (Tang et al. 2016a). Other laboratories have also demonstrated the localization of cellular formaldehyde in lysosomes detected by their own fluorescent probes (Brewer and Chang 2015; Cai et al. 2021; Ji et al. 2019; Xu et al. 2019; Xu et al. 2016).

The author considered that lysosomes play a key role in accommodation and transportation of formaldehyde in cells. This hypothesis is based on these observations: (1) Utilizing formaldehyde fluorescent probe, Chen et al. observed an increase in the intracellular formaldehyde located in the lysosome in the blood endothelial cell line (bEnd.3). (2) To demonstrate this result, they employed neuroblastoma N2a cells (N2a) from the mouse brain and observed the same result under oxidative stress (Chen et al. 2017). (3) LeuLeuOMe is the agent which can induce the permeabilization of lysosome membrane in bEnd.3. Introducing LeuLeuOMe leads to an increase in intracellular formaldehyde but a decrease in extracellular formaldehyde measured by microplate reader and high- performance liquid chromatography (HPLC). This is to say, lysosome cannot only accommodate endogenous formaldehyde inside a cell but also transport the cellular compound out a cell. (4) In order to get further data to support the hypothesis, Chen et al. isolated the lysosomes from the brain of rats which were operated on surgery with the chronic cerebral hypoperfusion because oxidative stress elevated endogenous formaldehyde levels in rats compared with SHAM controls. They found that the brain formaldehyde was significantly (P < 0.01) elevated in the lysosome compared to the cytoplasm (Chen et al. 2017). These data suggest that abnormal lysosome function is related to dysmetabolism of formaldehyde.

In fact, abnormal lysosomes increase as aging (Wyss-Coray 2016), and so does the endogenous formaldehyde (Tong et al. 2013). As previously reported (Wyss-Coray 2016), lysosome dysfunction results in protein aggregation and accumulation (Xiong and Zhu 2016). It is interesting to note that the accumulation of aggregated proteins may damage the function of lysosomal, which in turn induces the Tau protein aggregation, forming a vicious circle (Malik et al. 2019; Yan and Zheng 2021). Accumulating evidence has demonstrated that transcellular propagation and aggregation of mis-folded Tau resemble prion pathogenesis in the progression of tauopathies, including AD, with general molecular mechanisms involved with endosomal-lysosomal-exosome system (Arbo et al. 2020; Victoria and Zurzolo 2017; Vidyadhara et al. 2019; Yan and Zheng 2021). It is reasonable to hypothesize that endogenous formaldehyde is involved in protein aggregation as mentioned above. Dysmetabolism of formaldehyde should affect protein synthesis, modification, and degradation. Abnormal lysosomes should dysfunction in cellular formaldehyde metabolism and thus affect the scavenging of the abnormal biomacromolecules in the oxidative stress (Evans et al. 2016), in particular of abnormal proteins and their aggregation accumulation (He 2016).

6 NMDA Dysregulation in the Presence of Tau Phosphorylation and Formaldehyde

Although the relationship between formaldehyde and N-methyl-D-aspartate (NMDA) receptors has been deeply and widely studied in pain mechanisms for many years, research of the effect of formaldehyde on NMDARs which is associated with cognitive ability and impairment has started recently. NMDA receptors are crucial in activity-dependent synaptic changes and in learning and memory (Baez et al. 2018; Hayashi 2022). On the one hand, besides Aβ deposits, neurofibrillary tangles (NFT) containing hyperphosphorylated Tau protein are responsible for glutamatergic dysfunction, leading to NMDA-dependent Ca²⁺ influx into postsynaptic neurons and generating slow excitotoxicity process. Dysfunction of NMDARs may result in oxidative stress, impaired cognitive ability, and finally loss of neurons (Italia et al. 2022; Thakral et al. 2023). However, dysfunction of NMDARs leads to Tau hyperphosphorylation in rat prefrontal cortex and hippocampus in noise-induced animal model (Li et al. 2014). On the other hand, formaldehyde is able to bind to NMDARs directly. In 2008, Lu et al. have studied the effect of inhaled exogenous formaldehyde on learning and memory of mice. They considered the mechanism for gaseous formaldehyde-induced neurotoxicity is possibly related to oxidative damage, and the alteration of NMDA receptor regulation. Inhaled formaldehyde negatively affected learning and memory at a middle formaldehyde level without disturbance of other indoor air pollutants.

To study the effect of endogenous formaldehyde on cognitive abilities, Tong et al. (2011) used excess concentrations of formaldehyde to block the NMDA receptor and inhibit the formation of hippocampus long-term enhancement (LTP). They found that formaldehyde-suppressed NMDA receptors declines spatial learning and memory ability in rats. In the next year, Chi et al. (2012) observed that NMDARs and T-type Ca²⁺ channels may be involved in the elevation of [Ca²⁺]i in the cultured hippocampal neurons induced by a low formaldehyde concentration. Decreased viability of the hippocampus and downregulated expression of the NR1 and NR2B subunits of the NMDARs occurred in the treatment with chronic excess formaldehyde over 30 days (Tong et al. 2013). This is to say, ageing-associated formaldehyde metabolic dysregulation and accumulation probably impair memory by suppressing NMDA-receptors in brain (Kou et al. 2022; Tong et al. 2011, 2013).

As previously described, the effect of formaldehyde on normal or abnormal cognitive ability exhibits in a formaldehyde concentration-dependent manner. Formaldehyde metabolism is maintained at a homeostasis, and either shortage or excess of endogenous formaldehyde probably interferes with related functions (He et al. 2010). Physiologically, spatial learning activity rapidly elicits production of formaldehyde from sarcosine dehydrogenase (SARDH) in mitochondria (Ai et al. 2019). Increased formaldehyde can facilitate spatial memory formation through improving NMDAR currents. Pathologically, however, high concentrations of formaldehyde inactivates NMDA receptor by cross-linking NR1 subunits to NR2B (Fei and Tong 2020; Kou et al. 2022). Formaldehyde deficiency caused by mutation of the SARDH gene in mitochondria in children with sarcosinemia or mice with Sardh deletion may appear cognitive deficits (Ai et al. 2019). Those data indicate endogenous formaldehyde regulating cognitive abilities probably via affecting the NMDA receptors besides other pathways.

Tau also shows a chaperone-like interaction with DNA (Hua et al. 2003) and protein (Chen et al. 2000). Tau proteins can organize and repair DNA, showing its involvement in maintaining genomic integrity (Hua and He 2003; Chinnathambi et al. (2025a). Chinnathambi et al. (2025b) revealed the relationships between Tau and Nuclear pore complex components, and DNA in the context of AD, suggesting an insight into the pathomechanisms underlying Tau-induced neurodegenerative diseases and potential therapeutic targets.

7 Conclusion

Dysmetabolism of endogenous formaldehyde is regarded as one of the risk factors for the onset and progression of age-related cognitive impairments including Alzheimer’s disease and other neurodegenerative diseases. Excess extracellular and intracellular formaldehyde induces neuron dysfunction and death, involving the impairment of cognitive ability. Neural proteins, for instance, Tau protein, are prone to the reaction with formaldehyde, resulting in globular-like protein aggregation with cytotoxicity. In terms of the interaction between Tau protein and RNAs, it is reflected in phosphorylated protein-induced RNA accumulation, or RNA-induced protein accumulation, or their direct interaction, so as to explore strategies to prevent their accumulation and explore the treatment. As showed in Fig. 8.3, formaldehyde treatment inactivates Tau in its binding to microtubules, actin, and F-actin as well as suppresses Tau’s association with DNA and RNA (He et al. 2009; Hua and He 2003; Lu et al. 2013; Wang et al. 2006; Wei et al. 2008).

Fig. 8.3

Roles of MTBD and PRD of Tau protein. Tau protein interacts with tubulin, actin, DNA and RNA through its MTBD and PRD. However, formaldehyde suppresses the interaction of Tau with the macrobiomolecules by inducing Tau protein aggregation (He 2017)

Tau protein may be modified by formaldehyde in vivo, since the endogenous aldehyde comes from different and multiple sources such as food, oxidative stress, demethylation, and intestinal microbiota (Hu et al. 2016; Liu et al. 2017). The formaldehyde-treated Tau causes oxidative stress on neural cells and cell apoptosis. In fact, direct intervention of the reaction between formaldehyde and proteins, in particular of neuronal Tau resulting in cytotoxicity, should be addressed at the onset and in the progression of neurodegenerative disease, although a great number of researches have been carried out on phosphorylation and glycosylation catalyzed by kinases and enzymes and nonenzymactic glycation (see Chap. 10). The mechanism of formaldehyde-induced cognitive impairment involves the dysfunction of NMDA receptors caused by direct binding of formaldehyde to NMDA receptors or by inducing Tau hyperphosphorylation and Aβ deposition. At the same time, formaldehyde interacts with monoamine neurotransmitters, resulting in the inactivation of neurotransmitters such as catecholamine and serotonin, which contribute to understanding the dysfunction of synaptic transmission, as well as cognitive impairment (see Chap 3). Clarification of the pathomechanism of formaldehyde-modified Tau inducing cell death is beneficial to understand Tauopathies in the age-related cognitive impairment. Formaldehyde-induced protein aggregation and cell stress will be still as common models in the study of neurodegeneration.

Acknowledgments

All the grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_9

9. Cognitive Ability and Impairment Related to Formaldehyde

Rongqiao He1  

(1)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Imbalance of formaldehyde metabolism may be one of the various pathomechanisms involved in the onset and progression of age-related cognitive impairment. Provided evidence demonstrated that having been or being occupationally exposed to exogenous formaldehyde can affect cognitive performance. Elderly patients with the postoperative cognitive dysfunction (POCD) suffered from high levels of endogenous formaldehyde after their surgeries, but those without POCD did not. Monkeys fed with low concentration of methanol suffered from loss of working memory. Levels of hippocampal formaldehyde from the patient autopsy are significantly higher than those of age-matched normal controls. Using a double-blind experiment, the correlation between endogenous (urine) formaldehyde and general cognitive abilities was estimated in a community-based elderly population (n = 604). Urine formaldehyde levels were inversely correlated with the Montreal Cognitive Assessment (MoCA) scores of elderly participants. The concentration varied with demographic features: higher odds of a high formaldehyde level occurred among the less educated elderly population. Educational levels are strikingly correlated with the concentration of endogenous formaldehyde for the elderly living in local communities in Beijing. The epidemiological investigation showed that the average concentration of urine formaldehyde of the elderly increases with aging (>75 years old). In clinical study, the concentration of urine formaldehyde of Alzheimer’s patients is inversely correlated with their Mini-Mental State Examination (MMSE) scores. Urine formaldehyde levels were significantly elevated in subjective cognitive decline (SCD) group, compared with cognitively normal controls (NC), objectively defined subtle cognitive decline (Obj-SCD) and mild cognitive impairment (MCI) groups, suggesting that urine formaldehyde could be used as a noninvasive biomarker for early diagnosis before objectively cognitive decline and differential diagnosis of Alzheimer’s disease (AD) at different stages. In distinguishing normal cognitive control from AD patients, the areas under the receiver operating characteristic curves (AUC) of urine formate was 0.797, better than some plasma biomarkers such as Aβ and P-Tau, and similar to that of plasma neurofilament light chain (NfL; AUC = 0.768). We would like to emphasize that employing urine levels of both formate and formaldehyde may improve the accuracy of using the plasma biomarkers to distinguish AD stages. Therefore, endogenous formaldehyde and formic acid could be employed as noninvasive biomarkers for detecting, diagnosing, distinguishing, and monitoring age-related cognitive impairment.

Keywords

FormaldehydeFormic acidCognitive impairmentDysmetabolismConsciousness

Abbreviation

AD

Alzheimer’s disease

ADH5

Alcohol dehydrogenase 5

CSF

Cerebrospinal fluid

ELISA

Enzyme-linked immunosorbent assay

FAD

Formaldehyde dehydrogenase

FAD

Homolog of mammalian GSNOR

GSNOR

S-Nitrosoglutathione reductase (Formaldehyde dehydrogenase)

HPLC

High-performance liquid chromatography

MCI

Mild cognitive impairment

MMSE

Mini-Mental State Examination

MoCA

Montreal Cognitive Assessment

POCD

Postoperative cognitive dysfunction

PSD

Post-stroke dementia

SAMP8

Senescence-accelerated mouse prone 8

SAMR 1

Senescence-accelerated-resistant mice 1

SDS-PAGE

Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis

SSAO

Semicarbazide sensitive amine oxidase

VD

Vascular dementia

1 Introduction

Alzheimer’s disease (AD) is the most common form of senile dementia, affecting daily life of millions of aging people worldwide by deteriorating their working ability (Kalaria et al. 2008; Deardorff and Grossberg 2019; Emrani et al. 2020). Among many hypothetic pathomechanisms for age-related cognitive impairment, the hypothesis that “dysmetabolism of formaldehyde is involved in senile dementia” is gradually emerging in the progression of age-related cognitive impairment including AD and vascular dementia (VD) (He et al. 2010; Tong et al. 2017; Kou et al. 2022). Formaldehyde levels in urine of the patients are inversely correlated to their cognitive scores in clinics (Li et al. 2016b; Tong et al. 2017). We hope more researchers are aware of the role of formaldehyde and further demonstrate the hypothesis with basic and clinical researches now and in the future although significant progress has been made in the mechanism and double-blinded study of formaldehyde-induced dementia (Wei et al. 2022; Tang et al. 2023).

Formaldehyde, acting as a basic unit for many molecules in organisms (Pinto et al. 1980), is widely used in manufacturing/building materials and household products. Excessive formaldehyde exposure leads to severe health problems (Tang et al. 2009), including cognitive impairment (Marceaux et al. 2008; Shi and Wang 2013; Su et al. 2016) such as defect in learning and memory (Flyvholm and Menné 1992; Perna et al. 2001; Chen et al. 2023a, b). Intentional or unintentional uptake of excess formaldehyde or methanol (a precursor of formaldehyde) revealed marked decline in the neuropsychological integrity of participants (Chen et al. 2007; Maliutina and Taranenko 2014). At the biomolecular level, formaldehyde inactivates neuronal Tau (microtubule-associated protein) and induces the protein misfolding (Hua and He 2002) to form cytotoxic aggregates (Nie et al. 2007a, b). Excess formaldehyde leads Tau protein to lose protection of DNA and form stable aggregation as detected in Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis )SDS-PAGE) (Wei et al. 2008). Further investigation performed on changes in Tau conformation in the presence of formaldehyde demonstrated a “hydrophobic core” inside the stable aggregation (Nie et al. 2005). This is because the aggregation shields the proteolytic sites, so that its cytotoxicity is not easy to be cleared by the proteases. Recently, Tang et al. have preliminarily studied the location of cellular formaldehyde with fluorescent probes and found formaldehyde in lysosome, endoplasmic reticulum, and Golgi apparatus (Tang et al. 2016, 2023; Jian and Zhu 2016). Chen et al. discovered that formaldehyde is accommodated and transported by lysosomes (Chen et al. 2017). Furthermore, mitochondrion is also one of the sources in which electron-leak of the electron-chain produces H₂O₂ and ROS (Reshetnikov et al. 2020). By adding hydrogen peroxide to cell culture, Chen et al. (2017) observed a marked increase of formaldehyde level in cells. Mitochondrial complex I was found to act as a mediator in the regulation of formaldehyde production and detoxification (Bornstein et al. 2023; Wit et al. 2023). Although the toxicity of exogenous formaldehyde to human health has been widely studied (Golden and Valentini 2014), the effects of endogenous formaldehyde on our brain structure and function remain to be mysterious, in particular of the relationship between endogenous formaldehyde and cognitive ability (He 2016a).

In humans, however, endogenous formaldehyde is present in cells such as astrocytes and neurons, as well as cell microenvironment such as cerebrospinal fluid (CSF) (Li et al. 2020), blood, and urine (Yu et al. 2003; Li et al. 2008; Wang et al. 2022a). Human cells generate and degrade endogenous formaldehyde all the time (Shi et al. 2004). The concentration of endogenous formaldehyde tends to maintain equilibrium for a homeostasis through formaldehyde cycle (Tyihák et al. 1998: Burgos-Barragan et al. 2017) under physiological conditions. In other words, for normal people, his/her metabolic ability is effective and formaldehyde is quickly degraded to formic acid and then carbon dioxide and water. However, as aging or oxidative stress accumulating, the metabolism of endogenous formaldehyde gradually becomes imbalanced, resulting in chronic cognitive impairment (Tong et al. 2008, 2011a, b). In some sense, AD is considered as a dysmetabolic disease, for instance, the glucose dysmetabolism in brain (Crane et al. 2013). Formaldehyde might play a role in cognitive impairment when diabetes progresses and is complicated with dysmetabolism of the aldehyde (He 2016b). Evidence becomes more to support the viewpoint that accumulation of endogenous formaldehyde in the brain leads to neurodegenerative diseases (Nie et al. 2005; Chen et al. 2006; Miao and He 2012; Tong et al. 2013a; Wang et al. 2012; Chen et al. 2014; Rana et al. 2021; Xu et al. 2022). Furthermore, clinical investigations have shown that urine formaldehyde concentrations are significantly higher in patients with Alzheimer’s disease (AD) than in unaffected aged adults (Tong et al. 2011b). In this chapter, we would like to discuss the effects of endogenous formaldehyde on the cognitive ability and the cognitive impairment.

2 Endogenous Formaldehyde and Cognitive Ability of Normal Aging Population

2.1 Elevation of Formaldehyde as Aging

So far, not a few scientists have paid attention to the relationship between endogenous formaldehyde and cognitive function for normal population, since a considerable literature has been released on the detrimental effects of formaldehyde on DNA, proteins, neurons, respiratory system, brain, and so on. Epidemiological investigations have been performed and changes in the concentration of endogenous formaldehyde observed as aging and on clinical (Tong et al. 2013b; Yu et al. 2014; Wang et al. 2022a; Chen et al. 2022).

The average concentration of endogenous formaldehyde gradually increases as aging (>75 years old), from either overproduction or declined degradation of formaldehyde or both (He et al. 2010; Tong et al. 2013a; Kou et al. 2022). However, statistically significant differences in formaldehyde levels were only observed in participants over the age of 80 when compared to young adults. This seemed to be in consistence with the prevalence of AD which is about 2.2% for 65–69-year-olds, 3.3% for 70–74-year-olds, and 6.5% for 75- to 79-year-olds (see the website: Dementia Guide). No statistically significant difference in concentrations of formaldehyde was found between aged and young adults in a small portion of dementia participants. However, as aging, in the group of participants over 80 years old, the AD prevalence becomes as high as 11.6%, making the correlation of age and concentration of formaldehyde conspicuous. Consequently, over the past three decades, China has experienced a markedly rising burden of age-related cognitive impairment. Females suffered from more significant burden of dementia, but the potentially increasing dementia burden in males still needs estimating (Zhu et al. 2023). Therefore, one question needs to be answered: whether a correlation between endogenous formaldehyde and cognitive abilities persists in relatively healthy older adult populations.

2.2 Cognitive Ability of Elderly Is Related to Endogenous Formaldehyde

According to Madrid et al. (2008), indoor exposure to formaldehyde of school-age children could induce disruptive behavior disorders and learning problems, along with underlying stress disorders, anxiety, and depression. In order to clarify the effect of formaldehyde exposure on adults during their professional life, Letellier et al. recruited 75,322 participants with a median age of 57.5 years and 53% of them were women. The study found that 8% of them were exposed to formaldehyde during their professional life. In trial of this large sample of French adults (≥45 years of age), they provided evidence that having been or being occupationally exposed to formaldehyde can affect cognitive performance (Letellier et al. 2022). Higher level and longer duration of exposure were associated with cognitive impairment after controlling for socioeconomic factors and life-time occupational conditions. The risk of cognitive impairment was higher for recent exposure; however, time may not fully attenuate the formaldehyde-associated cognitive deficits. Similar condition of cognitive impairment from which recovery is difficult has been observed in monkey exposed to formaldehyde (Yang et al. 2014b). These results provide new evidence to further limit formaldehyde use and to target prevention efforts to the identified occupational groups.

The relationship between the concentration of endogenous formaldehyde and human cognitive ability has been studied in normal aging population (Yu et al. 2014). Since proteins interfere with formaldehyde detection, urine was analyzed instead of blood which is rich in serum protein. Compared with sampling blood, urine formaldehyde measurement has several advantages (Shao et al. 2011) including the noninvasive nature of sample collection and the presence of much fewer proteins. The correlation between urine formaldehyde and general cognitive abilities was estimated in a community-based elderly population in Beijing.

Yu et al. recruited 604 participants and divided them into three groups based on the urine formaldehyde concentrations: low (≤8.00 μmol/L, n = 192), medium (8.00–13.20 μmol/L, n = 200), and high (≥13.20 μmol/L, n = 212) (Yu et al. 2014). To clarify the relationship between endogenous formaldehyde and cognition, they analyzed data from previous work (Yu et al. 2012). Using the MoCA test, they found that the cognitive abilities decreased when formaldehyde levels increased [F(2, 597) = 11.17, P < 0.001]. Post-hoc Newman-Keuls comparisons showed that MoCA scores were markedly higher in the group with low concentration of formaldehyde than those in the group with medium or high formaldehyde concentrations (P < 0.05). That is to say, levels of endogenous formaldehyde are indeed correlated to the cognitive abilities of the aging participants from different communities in Beijing. Beside educational levels, Yu et al. measured the extent and direction of the correlation between social connection and cognitive impairment in different demographic characteristics such as age, gender, and residential region.

2.3 Educational Levels and Endogenous Formaldehyde

Yu et al. analyzed the correlation between concentrations of urine formaldehyde and the educational levels (years) of the aging participants in their youth. The endogenous formaldehyde concentrations [F(2, 601) = 1134.27, P < 0.001] and educational years [F (2, 597) = 27.05, P < 0.001] were significantly different among the groups (Yu et al. 2014). By using post-hoc Newman-Keuls comparisons, they also found that the group with low concentration of formaldehyde had more educational years than those with the medium or high concentrations of formaldehyde (P < 0.05). Moreover, residential regions were different among the three groups (χ2 = 154.84, df = 4, P < 0.001). Regarding the residential regions, the group with low concentrations of formaldehyde had the highest proportion of participants living in the new town (91.67%). In other words, those with the medium and high concentrations of formaldehyde were less educated and more likely to live in the old town or rural area, but they had comparable distributions of age and gender with the low group. Note that each group had similar numbers of participants to minimize statistical errors. Sample characteristics suggest that the correlation between the cognitive ability and endogenous formaldehyde of the old participants is related to their educational levels in youth (Yu et al. 2014) (Fig. 9.1).

Fig. 9.1

The correlation between urine formaldehyde concentrations and educational levels. The participants were divided into three groups based on the urine formaldehyde concentrations. Their educational years were statistically compared with the endogenous formaldehyde concentrations. The higher the concentrations of formaldehyde are, the less the educational years. FA, formaldehyde. This figure was referred to authors’ work (Yu et al. 2014)

Wilson et al. have studied the educational attainment and cognitive decline in old age. Education is robustly associated with the level of cognitive function but not with the rate of cognitive decline (Wilson et al. 2009). In Yu et al. investigation, by controlling age and gender, the MoCA scores were positively correlated (r = 0.581, P < 0.001) with educational years (Yu et al. 2014). Shpanskaya et al. have studied the relationship between educational attainment and hippocampal atrophy in the AD neuroimaging initiative cohort. A potential protective association between higher education and lower hippocampal atrophy in patients with AD appears to be consistent with prior epidemiologic data, linking higher education levels with lower rates of incident dementia (Shpanskaya et al. 2014). Longitudinal studies are warranted to confirm their findings. Partial correlation analysis also showed the inverse correlation of the urine formaldehyde concentration with the MoCA scores (r = −0.191, P < 0.001) and educational years (r = −0.288, P < 0.001) under the same conditions. To clarify whether the demographic variables, education and living region influence the correlation between urine formaldehyde and cognitive ability, Yu et al. performed univariate analysis, but they could not find any significant interactions between these variables in the whole sample. Furthermore, they employed linear regression analysis to assess the direction and strength of the association between these correlates and general cognitive abilities (Yu et al. 2014). The variable urine formaldehyde concentration was no longer significant after education was included in the models, indicating a mediating effect of education on the association between urine formaldehyde concentration and cognitive ability.

As described by Yu et al., the negative effect of elevated concentrations of formaldehyde could not be apparently observed on the cognitive abilities in the participants with higher educational levels (Yu et al. 2014). This is to say, education is able to counteract the negative effects of endogenous formaldehyde on neural connections or plasticity in subsample analysis. These data are coincident with the “scaffolding theory of aging and cognition” as described by Park and Reuter-Lorenz (2009). In their statement, scaffolding is a normal process involving the use and development of complementary, alternative neural circuits to achieve a particular cognitive goal, and extra learning, cognitive training, and exercise promote or repair the scaffolding during the aging process. Higher educational levels are most probably resulted from more learning, more engagement in intellectual activities, and more participation in cognitive training. More education is able to counteract the decline of cognitive abilities caused by elevated endogenous formaldehyde and to rescue the scaffolding noted here as neuroplasticity. Therefore, education should be one of the protective factors against the abnormal accumulation of formaldehyde and the corresponding cognitive decline. Furthermore, well-controlled cellular experiments and clinical studies have provided clearer results, suggesting that urine formaldehyde could be employed as a noninvasive marker for age-related cognitive impairment in patients with AD and/or VD (Tong et al. 2017; Wang et al. 2022a).

Ageing is a leading cause of the decline in cognitive abilities, and a major risk factor for age-related neurodegenerative disorders. As described by Cui and Xu (2018), age-related cognitive function is associated with DNA methylation. As aging, DNA methylation levels gradually decrease (Wei et al. 2017). Training in learning and memory is able to change DNA methyltransferase function and DNA methylation and demethylation in rodents’ brain, suggesting that learning improves the ability of DNA methylation and demethylation (Tong et al. 2013b, 2015). As shown in further investigation, increased DNA methylation was observed in hippocampal samples from spatially trained mice, and increased DNA hydroxymethylation was found in samples from mice trained using a visible platform (Torres and Kerr 2021). These studies showed that higher education levels are correlated with lower urine formaldehyde concentrations, which suggests that long-term learning and memory (over 16 years education) may improve regulation of methylation and demethylation which is involved endogenous formaldehyde metabolism.

Given the broad spectrum of age-related cognitive decline, what needs illustration is unlikely that a single biochemical mechanism can fully explain the effects across all individuals (Li et al. 2012). However, the metabolism of endogenous formaldehyde is not only involved in an exclusive pathway (see Chap. 2) but in many biological pathways such as oxidative stress (Kum et al. 2007; Evans et al. 2016), neuroinflammation, Aβ deposition, Tau hyperphosphorylation, methanol toxicosis (Li et al. 2008; Zakharov et al. 2017), acidosis by formic acid (Klaassen 2001), one-carbon cycle (Goldberg and Mateles 1975), and de/methylation of DNA, RNA, and histones (Su et al. 2015). Dysmetabolism of endogenous formaldehyde could affect a broad spectrum of metabolism in vivo. This is why dysmetabolism of endogenous formaldehyde is related to sporadic age-related cognitive impairment.

Formaldehyde is rapidly converted to formic acid, and then to 10-formyl-tetrahydrofolate (THF) in the presence of formyl-THF synthetase. 10-formyl-THF undergoes two pathways: one is oxidized to carbon dioxide, and the other is converted to 5-formyl-THF to participate methylation (Tyihák et al. 1998). Local acidosis resulted from formic acid plays a key role in damaging neural cells, for instance, the retina. The retina of human is very vulnerable to the acidosis caused by formic acid accumulation since primate has much lower THF levels than rodents (Klaassen 2001). Therefore, formaldehyde cycle (Tyihák et al. 1998; Chon et al. 2017; Burgos-Barragan et al. 2017) which is involved in folate cycle and methionine cycle (Chap. 11) should not be neglected.

3 Endogenous Formaldehyde and Cognitive Impairment

3.1 Formaldehyde Involved in Postoperative Cognitive Dysfunction

More than 10 years ago, my sister-in-law Ms. Yun Feng worked as a nurse supervisor in the operating room in the hospital of Sichuan Province, China. She told me that some of elderly patients can suffer from dementia after a major long-term operation. For example, an old woman has got her femoral head replaced with the artificial one by arthroplasty. Her cognition was impaired after the operation. As described by Moller et al., this is called the postoperative cognitive dysfunction (POCD), a decline in cognitive function following surgical procedures, a matter of concern for anesthesiologists and patients (Moller et al. 1998). POCD was present in 25.8% of patients 1 week after surgery and in 9.9% of those 3 months after surgery. The cognitive dysfunction is usually exhibited by patients in terms of failure to perform simple cognitive or mental tasks that were previously easily attainable (Hanning 2005). POCD is commonly seen in the elderly, which may be resulted from different causes such as oxidative stress (Xu et al. 2024), inflammation (Kong et al. 2024), and operative anesthetic side-effects (Zhu et al. 2024). A number of perioperative factors have been implicated, but high confidence evidence, for cause, prevention, or treatment is still lacking (Brown 4th and Deiner 2016). Studies on POCD have focused on the impact of increasing age or poor education, as well as perioperative factors including the types of surgery and anesthesia (Monk et al. 2008), hypotension during surgery (Newman et al. 2007), and postoperative complications (Moller et al. 1998). So far, the relationship between Alzheimer’s disease (AD) and susceptibility to or exacerbation of POCD is not well understood (Arora et al. 2014), though AD has been thought to be associated with POCD (Xie and Tanzi 2006).

Operation is a striking cause to trigger stress on the patient except for minimally invasive surgery. Formaldehyde plays a role in the oxidative stress (He et al. 2010). It was a hypothesis that the metabolism of endogenous formaldehyde could be changed during perioperation. In addition, no useful extracerebral diagnostic biomarkers have yet been identified as indicators of POCD though aging, duration of anesthesia, postoperative infections, and respiratory complications were regarded as the risk factors for POCD. Therefore, Wang et al. measured the concentrations of endogenous (urine) formaldehyde of the patients before and after operation to find out whether formaldehyde metabolism responded to operation (Wang et al. 2012).

Ninety-five patients (aged 65–80 years) were enrolled and scheduled for major orthopedic or abdominal surgery. Twenty-two young patients (aged 20–40 years) were recruited to undergo the same procedures as controls (Wang et al. 2012). To determine the presence of POCD, all participants received neuropsychological tests 1 day prior and one-week post-procedure, in which the criteria were employed as described (Moller et al. 1998; Monk et al. 2008). As mentioned by Su et al. (2011), midstream of morning urine was sampled 1 day before surgery and on day 1, day 2, and day 7 postoperation. Wang et al. observed that concentrations of urine formaldehyde of all participants either with or without POCD were markedly elevated on the first 2 days after surgery. On day 7, the average concentration of formaldehyde in patients with POCD was still significantly higher compared with that in patients without POCD (P < 0.01). This suggested that dysmetabolism of endogenous formaldehyde was related to postoperative cognitive dysfunction.

In contrast, the young participants did not show cognitive impairment after surgery, and thus none of them were diagnosed with POCD. As has been mentioned above (Tong et al. 2013a), the average concentration of endogenous formaldehyde was gradually getting higher as aging (>75 years old), showing a decline in the metabolic ability in formaldehyde as aging. Young participants had a high efficiency in metabolism of formaldehyde. Therefore, the concentration of urine formaldehyde of the young participants was significantly lower than that in the elderly (P < 0.05), although their formaldehyde levels in perioperative period were similar to the elderly without POCD. In other words, the patients with POCD had high concentrations of urine formaldehyde not only in the perioperative period but also on day 7 after surgery. The concentration of urine formaldehyde is suggested to be used as a biomarker along with neuropsychological assessments to assist the diagnosis of POCD (Wang et al. 2012).

3.2 Urine Formaldehyde Is Positively Correlated with the Cognitive Impairment of Alzheimer’s Patients

According to the “formaldehyde stress” hypothesis (He et al. 2010), chronic dysmetabolism of endogenous formaldehyde can cause abnormal changes in protein modification and conformation, resulting in reduced long-term potentiation (Tong et al. 2013a), Tau aggregation (Hua and He 2002) and hyperphosphorylation (Lu et al. 2013a, b), amyloid β deposits (Yang et al. 2014a, b), DNA damage (Lu et al. 2013a, b), and even cell death (Szende and Tyihák 2010), followed by associated cognitive disability. The association of endogenous formaldehyde with the severity of cognitive impairment was found in age-related dementia patients (Tong et al. 2011a). The ratio of elevation of urine formaldehyde was approximately ~40% among the patients who were investigated in small samples with either AD or VD.

Li et al. recruited 62 AD participants (81.05 ± 6.36 years old) from the Beijing Geriatric Hospital and 69 normal participants (67.33 ± 6.19 years old) from local community to investigate the relation of urine formaldehyde with cognitive impairment (Li et al. 2016b). The high-performance liquid chromatography (HPLC) coupled with 2,4-dinitrophenylhydrazine (DNPH) was also used to determine the concentration of formaldehyde (Su et al. 2011). The average concentration of urine formaldehyde (14.27 ± 5.15 μM for male; 13.76 ± 5.12 μM for female) of the AD patients was dramatically higher (P < 0.001) than those (10.18 ± 2.17 for male; 9.19 ± 3.28 for female) of the participants with normal cognitive scores. Consequently, participants (70–80 years old) were selected, and the concentrations of urine formaldehyde were compared between the patients and participants with normal cognitive ability. Although the age factor was excluded, the data also showed the same trend (Tong et al. 2013a), namely urine formaldehyde levels increased not only with aging (>75 years old) but also with senile dementia (Li et al. 2016b).

To further investigate the relationship between endogenous formaldehyde and cognitive impairment, concentration of urine formaldehyde was measured, and cognitive impairment was assessed. To increase the sensitivity of the detection, HPLC coupled with a fluorescent reagent of ampicillin (Luo et al. 2001) was employed to determine urine formaldehyde (Tong et al. 2011b). In the double-blind investigation with the Beijing Geriatric Hospital and Shantou University Medical College, Guangdong, a significant increase in urine formaldehyde levels in patients (n = 91) with AD and an increase but not significantly in patients (n = 50) with MCI were observed. The concentration of urine formaldehyde is inversely correlated with the scores of MMSE (Rs = −0.441, P < 0.00001). This demonstrated that urine formaldehyde could be used as a noninvasive biomarker for investigation, diagnosis, and monitoring of the efficacy of medicine for the patients with age-related cognitive impairment (Tong et al. 2011a, 2017).

By recruiting 629 participants from Sixth People’s Hospital (Shanghai) through the outpatient memory clinic, Wang et al. (2022a) observed that urine formaldehyde levels were significantly elevated in subjective cognitive decline (SCD) group, compared with cognitively normal controls (NC), objectively defined subtle cognitive decline (Obj-SCD) and MCI groups, suggesting that urine formaldehyde could be used as a noninvasive biomarker for early diagnosis before objectively cognitive decline and differential diagnosis of AD at different stages (Wang et al. 2022a). Determination of the specific and effective biomarkers may help identify asymptomatic patients and estimate of the risk of AD progression. The detection of urine formaldehyde might be considered to monitor changes in AD and reflect therapeutic effects. However, further investigation is needed to validate those results of the studies (Chen et al. 2022).

The result from determination of formaldehyde is somewhat unstable because formaldehyde is rapidly converted into formic acid in the presence of formaldehyde dehydrogenase (FAD) or alcohol dehydrogenase (Trivisano et al. 2015). Formate, however, is relatively stable in vivo since the conversion of formic acid consumes folate which is not so sufficient in primate in comparison with rodents (Klaassen 2001). Thus, a relatively lower rate of formate turnover occurs in human than in rodents, especially in the absence of folate (Pietzke et al. 2020; Sokoro et al. 2008). According to Wang et al., urine formate levels showed an overall upward trend with the progression of AD. Formate in urine is closely correlated with the ACE-III scores (Chinese version of Addenbrooke’s Cognitive Examination III), MMSE scores (Mini-Mental State Examination), and MoCA-B (Montreal Cognitive Assessment-Basic) time, respectively (Wang et al. 2022b). In distinguishing normal cognitive control from AD patients, the area under the receiver operating characteristic curves (AUC) of urine formate was 0.797, better than some plasma biomarkers such as Aβ and P-Tau, and similar to that of plasma neurofilament light chain (NfL, AUC = 0.768) (Wang et al. 2022b). We would like to emphasize that employing urine levels of both formate and formaldehyde may improve the accuracy of using the plasma biomarkers to distinguish AD stages. The dynamic changes of endogenous formaldehyde and formate in the AD continuum (serum data would be even better) can be combined with comprehensive evaluation of cognitive abilities, to deeply explore the relationship between the urine metabolome biomarkers relevant to AD may yield valuable mechanistic information for clarify.

3.3 Approximately 40% AD Patients with High Levels of Formaldehyde

Let us reconsider the investigation data from previous work. The conditions for recruitment of AD patients and age-matched participants with normal cognition were as described (Li et al. 2016b). The scattering diagram of the relation between MMSE scores and concentrations of urine formaldehyde for normal participants (panel a’, Fig. 9.2) shows approximately 9.26% of them are with high concentration of formaldehyde, much less than in AD patients (41.38%) (panel a, Fig. 9.2). Similar ratios can be observed in analysis of the data based on the gender of participants (panel b, b’, c, c’, Fig. 9.2). According to these data, dysmetabolism of endogenous formaldehyde cannot cover all AD patients. This is reasonable because the etiology of AD is so complicated that no single factor could explain the whole pathomechanisms, although formaldehyde hypothesis covers a small part of them. Approximately 9–10% of the age-matched participants as control showed their concentration of urine formaldehyde is higher than the normal. What can we do for the normal participants with high levels of formaldehyde? It is suggested to perform a tracking investigation for them to see whether high levels of formaldehyde in the participants are due to AD or some other causes.

Fig. 9.2

The correlation between urine formaldehyde and cognitive scores. The conditions for recruit of AD patients and normal participants were as described by Li et al. The MMSE scores and concentrations of urine formaldehyde were plotted in scattering points from AD patients (panel a) and normal participants (panel a’). The MMSE scores and concentrations of urine formaldehyde were plotted in scattering points from AD patients of female (panel b) and male (panel c) as well as normal participants of female (panel b’) and male (panel c’). The dash line represents the average concentration of formaldehyde for AD patients (Wang et al. 2017)

Let us further consider the relation between the endogenous formaldehyde and cognitive ability. The distribution of the data is markedly different between the AD patients and participants with normal cognitive ability. Approximately 40% of the total AD patients are with high levels of endogenous formaldehyde, either females (panels b, b’, Fig. 9.2) or males (panels c, c’, Fig. 9.2) are. In other words, ~60% AD patients were not related to the dysmetabolism of endogenous formaldehyde. They may suffer from other genetic or environmental factors since AD is resulted from numerous and multiple pathogens (Vigasova et al. 2021; Zubair et al. 2023). In short, a large sample (at least 3000 cases) analysis should be carried out to clarify the relationship between endogenous formaldehyde and cognitive impairment in the future.

4 Other Results for Endogenous Formaldehyde Related to Cognitive Impairment

4.1 From Primates

According to Li et al. (2020), the concentration of formaldehyde has age-associated changes in amyloid-β in CSF of rhesus monkeys. Their work showed the change in formaldehyde levels in CSF is consistent with the progression of AD. Tong et al. analyzed the formaldehyde in the autopsy hippocampus from AD patients. As shown in their results, the level of the hippocampal formaldehyde is significantly (n = 8, P < 0.05) higher than that of age-matched normal controls (n = 9). This appears that imbalance of formaldehyde metabolism occurs in the brain of AD patients. Note that the autopsy hippocampus tissues were provided by the Netherlands Brain Bank (Tong et al. 2015).

Yang et al. administered low concentrations of methanol, producing formaldehyde as an intermediate product (Dorokhov et al. 2015) in drinking water. This led monkeys to lose working memory in 2–3 months during the administration. Both senile plaque and Tau hyperphosphorylation could be observed in monkey brain hippocampus and cortex, while the administration was prolonged to 2–3 years (Yang et al. 2014a). Hu’s group demonstrated that formaldehyde can induce Alzheimer’s disease-like pathologies and cognitive impairments in nonhuman primates (Zhai et al. 2018).

4.2 From Rodents

4.2.1 Formaldehyde Dysmetabolism Related to Animal Cognitive Impairment

The concentration of brain formaldehyde for 10-month-old mice (C57BL/6 J) was significantly higher (n = 8, P < 0.01) than that for 3-month-old mice (Li et al. 2016b). Determination of hippocampal formaldehyde in SD rats (1-, 6-, 12-, and 24-month-old) showed the concentration was getting higher as the rats aged (Tong et al. 2013a). Formaldehyde in the brain of APP/PS1-transgenic mice elevated at early stage (Tong et al. 2011a, b). Liu et al. found that seven-month-old APP/PS1 mice have got elevated levels of formaldehyde in the cecum microbiota compared with age-matched C57BL/6 J wild-type mice (Hu et al. 2016; Liu et al. 2017). Interestingly, reversal of memory deficit is correlated to formaldehyde reduction in AβPPLon/Swe mice (Lu et al. 2021). All these data demonstrated that dysmetabolism of endogenous formaldehyde is associated with age-related cognitive impairment.

Yang et al. also fed mice (8-week-old male ICR mice from the Kunming Medical College, Yunnan, China) with methanol under the similar conditions. The mice, however, did not show senile plaques but exhibited Tau hyperphosphorylation in hippocampus and memory loss (Yang et al. 2014b). Intraperitoneal injection of formaldehyde induces memory loss and learning retardation. For example, according to the level of formaldehyde in the brain of the transgenic mice, normal mice were injected with formaldehyde (0.5 mM, intraperitoneal administration), and memory loss was observed in Morris water maze test (Yang et al. 2014a). Li et al. administered 4% NaCl in C57BL/6 J mice for 3 months and found an elevation of brain formaldehyde accompanied with decline of learning in “shuttle box” assay (Li et al. 2016c). Lateral ventricle injection of formaldehyde was used to establish AD-like cognitive disorders and oral administration of silibinin was observed to improve cognitive impairment (Wei et al. 2022).

4.2.2 Dysmetabolism of Formaldehyde in the Aging Mouse

The senescence-accelerated mouse prone 8 (SAMP8) has deficiency in learning and memory and appears to be an excellent model for blood–brain barrier damage in vascular dementia (Ueno et al. 2016). SAMP8 is a model to study age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer’s disease (Butterfield and Poon 2005). It is also used as a model to develop therapeutic interventions for AD (Morley et al. 2012). Senescence-accelerated-resistant mice 1 (SAMR1) which did not have distinct cognitive disorders (Butterfield and Poon 2005) were employed as a control for SAMP8 in cognitive impairment study. To test the metabolism of endogenous formaldehyde in the brain, Qiang et al. measured the levels of formaldehyde in the SAMP8 brain and the enzymes for formaldehyde metabolism. In order to study the relation of endogenous formaldehyde with cognitive impairment for SAMP8, 3-month-old SAMP8 was evaluated of their spatial learning and memory ability by performing the Morris water maze test. The concentrations of formaldehyde in the brain, liver, and kidney were measured, respectively, at the same time. The concentrations of formaldehyde in the brain and liver of SAMP8 were significantly higher than those in age-matched SAMR1. The concentration gradually increased from 1 month up to 10 months of age (Qiang et al. 2014). These data demonstrated that dysmetabolism of formaldehyde may occur with age in mice.

To investigate the dysfunction of formaldehyde metabolism, Qiang et al. analyzed enzymes functioning in synthesis or degradation of formaldehyde in the brain of SAMP8. They measured the activity and expression of an anabolic enzyme (semicarbazide sensitive amine oxidase, SSAO) and a catabolic enzyme (alcohol dehydrogenase III, ADH3). They employed real-time PCR, Western blotting, enzyme assays, and immunohistochemistry techniques in the analysis. In the brain of three-month-old SAMP8, the expression of SSAO significantly increased, along with a decline in mRNA, protein, and enzyme activity of ADH3, compared with age-matched SAMR1. The imbalance of these metabolic enzymes may represent a causal explanation for the observed formaldehyde elevation in the SAMP8 brain. Such increase could be responsible for the observed Tau hyperphosphorylation and aggregation (see Chap. 8), ultimately leading to cognitive impairment (Lu et al. 2013a, b). Again, cognitive impairment is related to dysmetabolism of endogenous formaldehyde in aging mice. In addition, using illumination with 630 nm red light to treat SAMP8 mice, Zhang et al. (2019) observed that the illumination can reduce oxidative stress and restore memory by photo-activating catalase and FAD (Tian et al. 2023).

Furthermore, the SAMP8 is thought as an excellent model for age-related cardiovascular alterations (Karuppagounder et al. 2017). Microcirculation dysfunction plays an important role in hyperphosphorylation of Tau, Aβ aggregation, and cognitive impairment induced by accumulation of formaldehyde (Chen and Su 2015). Dysfunction of blood vessels is involved in age-related cognitive impairment. For example, the microcirculation disorder is involved in AD, and stroke, blockage of blood vessel, or bleeding in the brain may contribute to VD. Microcirculation dysfunction is regarded as one of the most important pathologies such as senility, degeneration, and immune disorders. Cerebral circulation insufficiency, energetic dysmetabolism, hypoxia-ischemia, and metabolite accumulation in AD and VD have a close relation to microcirculation dysfunction (Lyu et al. 2022; Ashleigh et al. 2023). Taken together, this study gives an insights into the role of metabolic enzymes in age-related accumulation of formaldehyde and thus the establishment of neurodegenerative diseases such as AD and VD.

4.3 From Drosophila

To study the relation between formaldehyde dehydrogenase (FDH, homolog of mammalian, S-nitrosogluathione reductase, GSNOR) and memory, Hou et al. overexpressed FDH in the central nervous system and found defects of the visual pattern memory of Drosophila (Hou et al. 2011). The role of FDH in learning and memory was independent upon development. The memory defect induced by FDH overexpression was observed in the fan-shaped body but not in the mushroom body. The visual pattern memory defect could be rescued by co-expression with exogenous cGMP-dependent protein kinase (PKG) (Hou et al. 2011). Their work supports not only NO-cGMP-PKG pathway but also formaldehyde metabolism plays a role in learning and memory. Mice with adh3 gene knock-in (overexpression) showed a slowness in its learning and memory in Morris water maze test (our unpublished data). Reducing the levels of formaldehyde in normal Drosophila could also disturb the balance of formaldehyde metabolism, leading to memory decline. Wu et al. (2014) suggested that further investigation should be carried out to clarify whether overexpression of FDH interferes the metabolism of formaldehyde or affects the NO-cGMP-PKG pathway. However, Zhang et al. (2017) demonstrated that overexpression of FDH leads to cognitive impairment of adh3 gene knock-in mice (see Chap. 15).

Furthermore, formaldehyde improves the proliferation of N2a cells when its concentration is lower than ~0.01 mM, but suppresses the proliferation when it is higher than 0.05 mM (Wang et al. 2017). Formaldehyde in excess impaired the processes of N2a cells and neurites of primary cultured rat hippocampal neurons (Lu et al. 2013a, b). However, removal of formaldehyde markedly rescued and regenerated the processes of N2a cells (Yu et al. 2014). In fact, cells produce formaldehyde by themselves and the concentration is about 5 μM in the culture medium (Wang et al. 2017). These results demonstrated a negative correlation between the endogenous formaldehyde and general cognitive abilities. In other words, excess or deficiency of formaldehyde resulted from imbalance of metabolism could lead to decline of cognitive ability as shown in the diagram (Fig. 9.3).

Fig. 9.3

A putative relationship between endogenous formaldehyde and cognitive ability or impairment (diagrammatic drawing). We supposed that excess or lack of formaldehyde resulting from imbalance of metabolism could lead to dysfunction in cognitive ability, for instance, learning and memory. It has been accepted that excess formaldehyde in the brain impairs cognitive ability. However, overexpression of alcohol dehydrogenase 5 (ADH5) acting as scavenger of formaldehyde induces cognitive impairment for Drosophila though the FAD is associated with NO metabolic pathway. Similarly, the lifespan of Drosophila also shows in a formaldehyde-dependent manner: a slight increase of formaldehyde extends lifespan and a marked increase of formaldehyde shortens the lifespan (see Chap. 15; Li and He 2016)

5 Exogenous Formaldehyde Caused Cognitive Impairment

In the winter of 1993, a young chemical engineer and friend of mine happened to be exposed to the steam containing formaldehyde when he and coworkers were working on the synthesis of polyvinyl formal adhesive in a workshop in a far suburb of Beijing. In the pilot plant experiment, he was busy to monitor and control the polymerizing reaction between formaldehyde and polyvinyl alcohol in a 2-ton reactor. Two days after exposure to the steam with formaldehyde, his memory declined. I was deeply concerned about his resultant symptoms and health. I attempted to understand why formaldehyde exposure could induce memory decline. After that, I got down to investigate the relationship between formaldehyde and cognitive impairment.

Over 45 years ago, Karapetian reported the cases of nerve system lesions of workers who were exposed to organic chemicals including formaldehyde (Karapetian 1971). Kilburn et al. recruited 305 histology technicians and studied them by regression analysis with age, years of cigarette smoking, and hours per day exposure to formaldehyde and other solvents as major independent variables (Kilburn et al. 1987). The results showed that increased daily hours of exposure to formaldehyde were positively correlated with failure in cognitive tests such as reduced performance on visual memory and digit span. More studies of the effects of exogenous formaldehyde on the central nerve system were carried out by the group in the next few years, and exposure to exogenous formaldehyde causes cognitive impairment (Morton and Feldstein 1991; Kilburn 1994).

In 1990, a multispecialty panel of physicians evaluated a case series of 53 composite-materials (including formaldehyde) workers in a large aircraft manufacturing facility who filed workers’ compensation claims for illness labeled by the media as the “aerospace syndrome” (Sparks et al. 1990). Going up to space is a process where astronauts, exposed to hypomagnetic field, microgravity, and cosmic radiation, go through oxidative stress. As mentioned above, oxidative stress induces increased endogenous formaldehyde. Mei et al. (2024) used a mouse model of hindlimb unloading (HU) to simulate the effect of weightlessness on astronauts in space. They observed that the weightlessness induces oxidative stress and increases endogenous formaldehyde levels. Formaldehyde not only plays role in memory loss, but also in motor impairments under the weightlessness (Yao et al. 2021). That is to say, oxidative stress-derived endogenous formaldehyde may potentially serve as a crucial catalyst in memory decline either on the ground or in the space.

Epidemiological investigations and animal experiments all show that formaldehyde exposure has a relationship with memory and learning decline. Hawkins et al. reported the cases of two subjects who experienced persisting memory difficulties following inhalation of formaldehyde-soaked marijuana (Hawkins et al. 1994). Increased daily hours of exposure to formaldehyde were correlated with reduced performance on visual memory, story memory, digit span, pegboard, and sharpened Romberg, as well as with errors on trails (Kilburn et al. 1987). Because of the exposure to low-level neurotoxins mixed with formaldehyde, toluene, and acetone in nail studios, the workers had neurologic complaints as well as perceived problems with cognitive efficiency, memory, and learning (LoSasso et al. 2001). People exposed to indoor air after building renovation or in manufactured homes had neurobehavioral and neuropsychological deficiency though less severe but similar to those with occupational formaldehyde exposures (Kilburn 2000). Formaldehyde exposure in animal experiments showed psychotic disorders accompanied with pathologic and molecular changes of brains (Li et al. 2016a, b, c; Mei et al. 2016). Formaldehyde exposure impaired mice in spatial memory associated with hippocampal neuronal death and decrease of brain melatonin concentrations which is an antidepressant drug in clinic (Mei et al. 2016). Another study has shown that exposure to formaldehyde at 2.6–4.6 ppm inhibited the learning process of rats which were trained in an operant conditioning task, and the data also indicated the possible neurotoxicity of formaldehyde exposures (Pitten et al. 2000). A formaldehyde concentration of 0.5 ppm and above significantly affected the locomotor behavior of adult male and female rats in the open field. After inhaling formaldehyde at 5–6 ppm for 2 h/day and a total of 10 days, the rats used significantly longer time to find the target in the water maze experiment than controls, while the histopathology changes were not observed (Malek et al. 2003). Inhalation of 2 ppm formaldehyde reduced body weight, increased levels of depression-like behavior, and impaired novel object recognition in mice (Li et al. 2016a, b, c). Inhaling 2.44 ppm of gaseous formaldehyde negatively affected learning and memory in mice but lower levels of formaldehyde did not (Lu et al. 2008). Experimental evidence has also demonstrated that occupational exposure to formaldehyde is associated with human cognitive impairment (Letellier et al. 2022; Liu et al. 2023).

So far, it has been widely known that exogenous formaldehyde exposure induces human cognitive impairment and animal memory loss (Bernardini et al. 2022; Kou et al. 2022). Inhalation of exogenous formaldehyde is different from the effect of the endogenous formaldehyde on human health because the inhaled steam goes through our respiratory system and then dissolves in blood. It may damage human respiratory and blood compositions and even induces cancers (Duong et al. 2011). Acute formaldehyde exposure at 5 ppm results in decreased motor activity and increased levels of dopamine (DA) together with its enzymatic metabolites in the hypothalamus of rats (Boja et al. 1985). Furthermore, exposed to the air containing formaldehyde (10.2 ppm, 4 h daily) for 7 days may impair olfactory bulb and hippocampus in rats (Li et al. 2010, 2015, 2016a). According to the World Health Organization, formaldehyde levels should not exceed the threshold value of 0.1 mg/m³ (0.08 ppm) for a period of 30 min (La Torre et al. 2023). Zhang et al. reported the impairment of olfactory function and change of SNAP25 proteins in olfactory bulb under repeated formaldehyde inhalation (Zhang et al. 2014; Foveau et al. 2016). In fact, the olfactory impairment (Hu et al. 2017) and odor identification deficit in MCI and AD may be associated with hippocampal and deep gray matter atrophy (Hagemeier et al. 2016). The formaldehyde-induced brain impairment through inhalation should be one of the risk factors related to central nervous system damage and cognitive impairment.

6 A Biomarker for Age-Related Cognitive Impairment Including AD and VD

Tong et al. showed the elevated concentrations of formaldehyde in patients who had got diabetes or hypertension with cognitive impairment. But the formaldehyde elevation could not be observed among the patients without dementia symptoms (Tong et al. 2011b). Chronic inflammation is involved in the progression of both AD (Sawikr et al. 2017) and VD (Rosenberg 2017). SSAO also acts as a factor related to inflammation (our unpublished data). As described by Chen et al., formaldehyde actually acts as a biomarker for inflammation in the oxidative stress (Chen et al. 2017). Thus, Tong et al. have investigated the relationship between morning urine formaldehyde concentration and cognitive impairment in patients with post-stroke dementia (PSD) or AD in this cross-sectional survey for 7 years (Tong et al. 2017).

They assessed the participants’ cognitive abilities (n = 577) by MMSE and divided them into four groups: control (n = 231), stroke (n = 61), PSD (n = 65), and AD (n = 220). Gender and age-matched participants (n = 42 in each group) were employed from the four groups above. Using an enzyme-linked immunosorbent assay (ELISA) and HPLC, they analyzed the expression levels of SSAO and concentrations of formaldehyde in the blood and urine, respectively. It was demonstrated again that the morning urine formaldehyde levels are inversely correlated with MMSE scores (Tong et al. 2011b). An increase in the concentration of urine formaldehyde could be observed, which may be resulted from upregulation of SSAO in blood. The threshold value (the best cutoff value) of the formaldehyde concentration for predicting cognitive impairment was 0.0418 mM in patients with PSD (sensitivity, 92.3%; specificity, 77.1%) and 0.0449 mM in those with AD (sensitivity, 94.1%; specificity, 81.8%) (Tong et al. 2017). This is to say; the overnight fasting urine formaldehyde can be used as a potentially noninvasive biomarker to evaluate the likelihood of ensuing cognitive impairment for AD and VD. VD could be identified by the patient’s history who had suffered from stroke before. VD could also be distinguished by brain imaging including magnetic resonance imaging (MRI)-based cerebral lesion location and its association with cognitive decline (Quinn and McCleery 2017). The feature of formaldehyde as a biomarker is dependent upon its role in the inflammation and oxidative stress, when SSAO is activated. As described by recent studies, not only formaldehyde but also formate is associated with age-related cognitive impairment (Wang et al. 2022b) and stroke which is the key cause for vascular dementia (Di et al. 2022). Please see Chap. 13 for details on the relationship between vascular dementia and formaldehyde as well as formate. That is to suggest, elevation of endogenous formaldehyde could remind us that there occurs the oxidative stress and inflammation in the aging brain.

7 Consciousness Impairment and Formaldehyde

7.1 Definition of Consciousness

Although consciousness has multiple definitions (Wang and Cui 2023), consciousness can be described as “a basic brain function that an individual perceives the existence (reality) of oneself and one’s environment” (He 2015a). In other words, consciousness works for a person to realize the existence of himself or herself under wakefulness. The perception of the existence is the brain’s fundamental function for attention, learning, memory, thinking, cognition, etc., because these activities are performed in the presence of the consciousness (He 2015b).

7.2 Consciousness Impairment

My mother (Xiao-Wen He, born on 09/Mar/1917, a tailor) suffered from age-related cognitive impairment. She (aged 91, 26/June/2008) died of heart attack with hypertension. After she got senile dementia, the concentrations of her urine formaldehyde were high (17.12 ± 3.92 μM) analyzed with HPLC coupled DNPH, compared with that of normal control (9.61 ± 2.90 μM) (Li et al. 2016b; Su et al. 2011). This suggested a possible relation between the dysmetabolism of endogenous formaldehyde and her dementia. I lived with her in one apartment as she gradually became dementia. I had observed some of her behaviors that might be related to consciousness impairment in her last life.

She had suffered from loss of memory without dyskinesia symptoms. She could not recognize my eldest brother first, then my second elder brother, and myself at last. I had to employ a family nurse to take care of her. At early stage, she occasionally forgot switching off running water or natural gas in the kitchen. Later, her symptoms became worse. Fortunately, our apartment was not on fire because no one smoked in my family, but she forgot turning off the running water and flooded the apartment of our neighbor’s downstairs for several times. Apart from loss of memory, my mother had got spatial cognitive impairment and usually lost her way home (Fig. 9.4). I had to look for her when she got lost. One day, she was lost again in the street in Zhongguancun in Haidian District (Beijing). I rode a bike, looked for her, and finally found her. On the way home, I asked her, “Where are you going?” She answered, “I am going home.” I said, “You may follow a different way home (in Beijing).” She went on, “I know where my home is. But the way to ‘Goli Gate’ disappeared!” I continued, “This is Beijing.” She responded, “Here, it’s Feng town.”

Fig. 9.4

Wrongly perceiving the reality for oneself spatial position in street. Consciousness is a brain function to perceive the presence of oneself and one’s environment (He 2015a). The perception of the reality is the brain’s fundamental function for attention, learning, memory, etc., because these activities are performed in the presence of the consciousness (He 2015b). An age-related cognitively impaired patient was walking in the street of the Haidian district in Beijing but was looking for the way home in her childhood in the past time (Goli Gate in Feng Town). She had a wrong perception of the reality of her spatial position and took Haidian district for Feng Town which is about ~830 kilometers far away in Liaoning Province. Summer Palace in Beijing is shown in the direction indicator

Then I understood why she lost in Beijing and could not find the way home. Where is the Goli Gate? The gate is in the Feng town in Liaoning province ~830 kilometers away from Beijing! She in person was in Beijing (her present city), but hallucinated in Feng town. Although she was in Beijing, she was still trying to find the way home in her childhood near the Goli Gate. In fact, she could remember and describe the way to the Goli Gate in her hometown.

On the basis of Hebb’s theory, neurons in brain are activated and connected with other neurons, forming a neural network when our brains learn something new (Bear et al. 2016). The cell assembly for the memory of her hometown was still stored in her mind, which may be activated by some scenery looking like her hometown in the presence. For the impression on the present city, those connections were much weaker than those for her hometown, since she had been in Beijing only 1 year more. Moreover, she had also got MCI, leading to dysfunction in the cell assembly. Thus, she wrongly perceived the way home in Beijing at the present for that in her hometown. The cell assembly for the memory of the street in Beijing had not been formed to retrieval of memory because of her cognitive ability impaired. At that moment, in her mind, she herself was still living in her hometown, suggesting a wrong perception for the reality showing her consciousness impairment. Since consciousness is the fundamental function of the brain, consciousness impairment inevitably affects learning and memory.

I am concerned about whether dysmetabolism of formaldehyde affects human’s consciousness. At least, we can see, a deeply drunk man with alcohol (the intermediate metabolite is acetaldehyde) shows transient consciousness disorders. My mother had got high levels of endogenous formaldehyde, which was stronger toxic than acetaldehyde. Mice injected with formaldehyde showed spatial disorder that is related to memory loss as mentioned above (Tong et al. 2013b). We did not have any evidence to support this hypothesis yet. Therefore, it is far-fetched to say dysmetabolism of formaldehyde is related to consciousness impairment, which needs to be further investigated and clarified.

7.3 Consciousness Impairment Occurring at Late Stage of AD?

A famous painter Utermohlen’s self-portraits showed his perception of himself at different stages of AD. Harrison used AD as an exemplar of suffering and described a creative teaching strategy using nine self-portraits that chronicle American-born artist William Utermohlen’s deterioration from the disease (Harrison 2013). This is an extremely great valuable case to describe an AD patient’s recognition and perception of himself. Along with the progression of his disease, he gradually lost his recognition and perception of himself, his reality (existence). Eventually, he lost the awareness and consciousness on himself.

Auguste Deter was the first patient who had been diagnosed with AD (Alzheimer et al. 1995). Besides memory loss, for instance, she nagged, “I have lost myself,” and when asked to write her name, she also suffered from delusion. As described by Maurer et al., “When he released her, she would run out screaming, ‘I will not be cut. I do not cut myself’ (Maurer et al. 1997).” I am not sure what caused her to have such fear. However, as described, she had got delusion or illusion (Heydrich et al. 2010), which could be related to disorder of consciousness. A disorder of consciousness makes a person to feel fear. The fear was aroused by wrong perception of the existences such as a beast attacking, the vicious enemy coming, and calamity approaching. Under disorder of consciousness, the patient could wrongly perceive the delusive reality including oneself and one’s environment.

7.4 A Hypothesis for MCI Due to AD

At early stage of AD, patients may not show symptoms of consciousness disorders. As a clinical case, a retired surgeon (male, 83 years old) in the People’s hospital in Deyang city (Sichuan) has got MCI, and he can still take care of himself. Curiously, although he is capable of reading out the time on a digital-watch, he has become unable to read out time on a pointer-watch since last year (Fig. 9.5). In other words, he is still able to perceive and recognize time by numbers but not in pointers. His brain could not calculate and convert the time into a digital representation according to the position of the long and short hands on the watch. That is to say, he suffers from disorders with cognitive function, but not yet with consciousness.

Fig. 9.5

Cognitive disorders in reading time by pointer watch. Here is a case that a surgeon who has got MCI is able to read out time by digital watch, but unable to read out time by pointer watch, suggesting some disorders in his cognitive ability of calculating time by perceiving the pointer’s position on the watch

Here, I would like to propose a hypothesis that a patient with MCI due to AD may have his/her consciousness mildly impaired because consciousness impairment means disorders of basic function of the brain. For some cases, memory loss and learning decline could be resulted from consciousness impairment. It is difficult for us to intervene and ameliorate the basic function impairment. However, a patient simply suffer from mild impairment of memory alone should not have problems in consciousness.

7.5 A Hypothesis for AD Resulted from Formic Acid-Accumulated Chronic Acidosis

We consider that chronic accumulation of formic acid and the resultant chronic acidosis in brain, which gradually disturbs a series of molecular pathways, damages neural cells and disrupts neural connections, may act as a risk factor for the onset and progression of neurodegenerative diseases including AD. As described previously (Klaassen 2001), the ability of clearing formic acid is much lower in human brain than in the rodents. Thus, the chronic accumulation of formic acid resulted from the imbalance of formaldehyde metabolism may cause acidosis in human brain (Sohor et al. 2023). This may be why human brain is vulnerable to low concentrations of methanol or formaldehyde in which formic acid-accumulated acidosis damages neural connections and cells. Measurements of pH values of cerebral spinal fluid of postmortem and brain of C57BL/6 mice indicated that the pH of the brain decreased in aging people and Alzheimer’s disease patients including intracellular environment (Prasad and Rao 2018; Decker et al. 2021). As reported by a systematic review and meta-analyses of postmortem (Hagihara and Miyakawa 2024), decreased brain pH is correlated with progression of AD neuropathology. Endogenous formaldehyde increases as aging and in Alzheimer’s patients as well as the hippocampus of postmortem (Tong et al. 2011b, 2013b). We have some suggestions for intervening cognitive impairment associated with formaldehyde dysmetabolism: to exercise regularly to promote the ability of formaldehyde metabolism, to drink water and tea properly to enhance clearing endogenous formaldehyde and other metabolic products, to orally take lumbrokinase capsule to improve blood circulation, especially the microcirculation, and to reduce oxidative stress, yield of formaldehyde and formic acid in brain (Fig. 9.6).

Fig. 9.6

A putative scheme of formic acid-induced chronic acidosis in brain. Chronic acidosis in brain may be resulted from formic acid accumulation, chronic dehydration, and other pathways (Tanaka et al. 2022)

As brain’s aging, formic acid and the other metabolic by-products continue accumulating, brain tissues become more acidic. The brain’s internal environment is increasingly hostile to the survival of nerve cells. This is one of the reasons why neural stem cells are not effective in treating Alzheimer’s disease. On the other hand, survival of neural stem cells requires a variety of inducers and cofactors, and the deteriorating internal environment also affects the expression of those factors. Therefore, it is necessary for us to remove formic acid, formaldehyde, and other metabolites, which can help to improve the internal environment for nerve cells. This, however, requires improving the function of blood microcirculation in the brain.

As we know, one neuron is at least able to connect with thousands of other neurons. How can a transplanted neural stem cell replace the dead neuron correctly and precisely reconnect with the thousands of other neurons? To form those connections between a transplanted stem cell and the neurons to recover the original connections should be impossible in the aged brain, especially under acidic and inflammatory conditions. This involves not only the formation of neural network connections, but also the survival of stem cells. Recently, many laboratories reported that there are immature neurons in human hippocampus across lifespan (Ayhan et al. 2021; Zhou et al. 2022; Petrelli et al. 2023). It is a hypothesis here. If there were some immature neurons in the aging hippocampus, the immature neurons may have their neurites attaching on those of matures (Fig. 9.7). The attaching sites kept in silence, which had not yet been a synapse and have no communications transporting before the immature neuron was activated. Those touchments had formed during the development of brain, and they could not be activated to form the synapse until some of mature ones were dead. Once the touchments were activated under some conditions, the immature neurons could have opportunities to correctly take over the connections between the dead neurons and other neurons at least partially. Otherwise, it could be difficult to reconstruct those correct connections between immature and mature neurons.

Fig. 9.7

A hypothesis for connections between mature and immature neurons in the hippocampus. There could be numerous attachments (red point) between immature (blue cell) and mature (yellow cell) neurons if there were immature ones in aging hippocampus. The attachments had no communications when the immature neurons kept in silence. Those attachments would be activated to form synaptic communicating with other neurons when those immature neurons were converted to mature ones. For this, an activated immature neuron could have an opportunity to connect with other neurons correctly and precisely. Thus immature neurons can at least partially take over the connections between the dead neurons and survival neurons

8 Prospective

Metabolism of endogenous formaldehyde is maintained at homeostasis under physiological state, which is involved in multiple functions, especially cognitive abilities. We hypothesized that imbalance of the formaldehyde metabolism may cause cognitive impairment besides other dysfunctions. This viewpoint is based on these observations as follows:

First, the concentration of brain formaldehyde of mice and rats increases as they age (Tong et al. 2013a; Li et al. 2016a, b, c). A seven-month-old APP/PS1 mouse has got elevated levels of formaldehyde in the cecum microbiota compared with age-matched C57BL/6 J wild-type mouse (Liu et al. 2017). Reversal of memory deficit correlates to formaldehyde reduction in AβPPLon/Swe mice (Lu et al. 2021). Monkeys fed with water containing a low concentration of methanol suffered from working memory loss in 3 months during the administration (Yang et al. 2014a, b). Formaldehyde induces AD-like pathology and cognitive impairment in nonhuman primates (Zhai et al. 2018). Age-associated changes in amyloid-β and formaldehyde concentrations were observed in CSF of rhesus monkeys (Li et al. 2020).

Second, the average concentration of urine formaldehyde of the elderly increases with aging (>75 years old) in a small sample investigation (Tong et al. 2013b). The cognitive ability of the normal elderly is inversely related to the level of endogenous formaldehyde (Yu et al. 2014). Educational levels are strikingly correlated with the concentration of endogenous formaldehyde for the elderly living in local communities in Beijing (Yu et al. 2014). The concentration of urine formaldehyde is inversely correlated with MMSE scores for AD patients in clinics (Tong et al. 2011b). Levels of hippocampal formaldehyde from the patient autopsy are significantly higher than those of age-matched normal controls (Tong et al. 2015). High levels of urine formaldehyde could be observed in the old patients with POCD after 1 week of their surgery, but not in those without POCD (Wang et al. 2012).

Third, using meta-analysis, Chen et al. (2022) considered urine formaldehyde levels as a potential diagnostic accuracy biomarker in AD. Urine formaldehyde levels were significantly elevated in SCD group, compared with NC, Obj-SCD, and MCI groups (Wang et al. 2022a), suggesting that urine formaldehyde may be used as a noninvasive biomarker for early diagnosis of AD at different stages. In distinguishing normal cognitive control from AD patients, the areas under the receiver operating characteristic curves (AUC) of urine formate was 0.797, better than some plasma biomarkers such as Aβ and P-Tau, and similar to that of plasma neurofilament light chain (NfL; AUC = 0.768) (Wang et al. 2022b). We would like to emphasize that employing urine levels of both formate and formaldehyde may improve the accuracy of using the plasma biomarkers to distinguish AD stages. Therefore, endogenous formaldehyde and formate could be employed to screen for age-related cognitive impairment in epidemiological investigations for large populations, followed by identification of AD from VD in further examination.

Finally, the cell assembly is a complexed neuronal network because one neuron can connect with other neurons over one thousand. Each neuron is involved a complexed network, namely one neuron, one network. For example, a cell assembly for the memory of one’s hometown forms such a complicated neuronal network, which is connected with an assembly for the memory of the hometown’s streets, and also with those assemblies for community, family, family members’ faces, and so on. Networks form precise and accurate connections, working at a homeostasis. Excess formaldehyde may affect the connections between neurons by disrupting synapses and impairing cell viability, to disturb the balance the of the neuronal network for cognitive ability and consciousness.

Acknowledgments

I would like to thank Dr. Jing Lu who works in the Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Melbourne, Australia, for her language editing. All grants supporting this project are listed in the Preface of this book.

Funding Interests

No other funding interests at all.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_10

10. Amyloid β Deposition, Tau Phosphorylation, ApoE4 Dysfunction, and Formaldehyde

Jing Lu¹ and Rongqiao He2  

(1)

Tianjin Institute of Infectious Diseases, The Second Hospital of Tianjin Medical University, Tianjin, China

(2)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with a relentless progression. The development of AD is associated with amyloid-β (Aβ) peptide deposition in senile plaques and hyperphosphorylated Tau protein in neurofibrillary tangles (NTFs) in the AD patients’ brain as well as ApoE4 acting as a risk factor. Aβ accumulation occurs in early preclinical stage as a trigger factor for AD pathogenesis followed by silence of synapses and Tau protein hyperphosphorylation. However, what triggers Aβ deposition and Tau hyperphosphorylation is still under investigation. Recent studies showed that formaldehyde may play a pivotal role in the development of age-related neurodegenerative diseases. In this chapter, we introduce recent progresses on production and accumulation of formaldehyde with ageing and the signaling pathways of formaldehyde leading to dysfunction and aggregation of nuclear Tau protein, Aβ deposition as well as dysfunction of ApoE in vitro and in vivo. Formaldehyde acts as an effective trigger of Tau hyperphosphorylation in neuronal cell lines, primary cultured neurons, mouse brains, and monkey brains. Formaldehyde activates Tau phosphorylation kinases including glycogen synthase kinase 3 beta (GSK-3β), Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), and suppresses protein phosphatase 2A (PP2A). In primates (Macaca mulatta) experiments, feeding methanol in drinking water and the chronic intracerebroventricular (i.c.v.) injection of formaldehyde can induce AD-like disorders such as memory decline, Aβ deposition or plaques, Tau hyperphosphorylation and (neurofibrillary tangle (NFTs))-like changes, as well as gliosis in hippocampus and cerebral cortex, similar to AD-like changes in mouse experiments under the same conditions. The measurements of naturally aged monkeys demonstrated that concentrations of formaldehyde are associated with changes in amyloid-beta in cerebrospinal fluid (CSF) of rhesus monkeys as aging. The dysmetabolism of endogenous formaldehyde might start to occur in the early stage of age-related cognitive impairment as formaldehyde disturbs human brain functions in multiple pathways.

Keywords

FormaldehydeMethanolTau hyperphosphorylationNeurofibrillary tanglesTauopathyAmyloid βSenile plaqueCognitive impairmentApoE4NeuriteNeuronal processesCell deathMouse modelNonhuman primateDephosphorylationPathology

Abbreviations

A

Aβ

Amyloid beta

AD

Alzheimer’s disease

C

CaMKII

Ca2+/calmodulin-dependent protein kinase II

CDK5

Cyclin dependent kinase 5

CSF

Cerebrospinal fluid

D

Dyrk1A

Dual specificity tyrosine-phosphorylation-regulated kinase 1A

G

GSK-3β

Glycogen synthase kinase 3 beta

GFAP

Glial fibrillary acidic protein

L

LOAD

Late-onset AD

LTD

Long-term depression

N

NFT

Neurofibrillary tangles

NMDAR

N-methyl-D-aspartate receptor

NR1

N-methyl-D-aspartate, subtype 1

NR2B

NMDAR subtype 2B

P

PHFs

Paired helical filaments

PP2A

Phosphoseryl/phosphothreonyl protein phosphatase-2A

S

SSAO

Semicarbazide-sensitive amine oxidase

T

ThS

Thioflavin S

V

VSDRT

Variable spatial delayed response task

1 Introduction

In 1901, German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer’s disease (AD). Alzheimer found senile plaques and neurofibrillary tangles (NFTs) on examining the patient’s brain after she died in 1906 (Alzheimer 1907). These became the hallmarks of AD as known by scientists today (Ballard et al. 2011). AD is a progressive, irreversibly neurodegenerative disorder characterized by extracellular deposits of β amyloid (Aβ) peptides in senile plaques (Glenner and Wong 1984) and intracellular aggregates of hyperphosphorylated Tau protein in NFT in patients’ brain. Genetically mutations in Tau and amyloid precursor protein (APP) are associated with the early onset of this disease; apolipoprotein E gene with allele ε4 called ApoE4 is a known risk factor. Accumulation of Aβ has long been considered a leading hypothesis in the early onset of the pathology. Aβ deposition not only disrupts function of neural cells but also triggers hyperphosphorylation of Tau (Oliveira et al. 2015), for instance a ceramide-Aβ-hyperphosphorylated Tau cascade ends up with neuronal death (Jembrek et al. 2013). However, it is increasingly evident that Tau hyperphosphorylation plays a role in destabilization of microtubule assembly, loss of DNA protection, and disturbance of axonal transport, thus it is also non-negligibly detrimental in the neurodegenerative process.

Abundant work has been carried out to clarify what triggers or induces hyperphosphorylation of Tau (Su et al. 2016). The early stages of AD including preclinical AD are pathologically characterized by the formation of mature NFTs in entorhinal cortex and phenotypically characterized by disorientation and confusion when navigating familiar places (Lithfous et al. 2013; Allison et al. 2016). The medial entorhinal cortex contains specialized neurons called grid cells which form part of the spatial navigation system (Fyhn et al. 2004; Hafting et al. 2005). Fu et al. have given the evidence that Tau pathology initiated in the entorhinal cortex could lead to deficits in grid cell firing and underlie the deterioration of spatial cognition seen in human AD (Fu et al. 2017). Hyperphosphorylated Tau often first occurs in the entorhinal cortex layer II (ECII) and spreads to the CA1 field of the hippocampus. Using pyramidal neurons with Wolframin-1-expressing (Wfs1+) which functionally modulates hippocampal CA1 neurons, Delpech et al. (2021) demonstrated Tau transfer from the ECII to CA1 in mouse brain, providing an early Braak stage preclinical AD animal model.

Etiological factors inducing Tau hyperphosphorylation have been widely investigated, including gene mutation (Kar et al. 2005), changes in epigenetics (Bufill et al. 2013), oxidative stress (Chen N et al. 2012a, Chen NN et al. 2012b), inflammation (Barron et al. 2016), tumor or cancer (Serrano et al. 2010), metal ions (Cai et al. 2011; Zhao and Wan 2012), insulin imbalance (Planel et al. 2007; Kim et al. 2009; Qu et al. 2011), starvation (Yanagisawa et al. 1999), some toxicants (Chen et al. 2012a, b), advanced glycation end-products (Li et al. 2012), anesthesia (Run et al. 2009; Whittington et al. 2011), food ingredient (Monte 2012), drug usage (Rahman et al. 2009; Kim et al. 2012), and imbalance of intestinal microbe flora (Hu et al. 2016). Recently, microcirculation dysfunction especially elevation of formaldehyde is considered playing important roles in hyperphosphorylation of Tau, Aβ aggregation, and cognitive impairment (Chen et al. 2015). As we know, microcirculation dysfunction is regarded as one of important pathologies of senility, degeneration, immune disorder, and many other diseases. Cerebral circulation insufficiency, energetic dysmetabolism, hypoxia-ischemia, and metabolites accumulation in AD have a close relationship with microcirculation dysfunction (Nobutoki and Ihara 2015).

To investigate aldehydes-induced Tau phosphorylation and aggregation in this laboratory, Luo et al. employed acetaldehyde and glutaraldehyde in comparison to ethanol and methanol (He et al. 1998; Luo and He 1999). We have observed that aldehyde could affect phosphorylation of Tau catalyzed by neuronal Cdc2-like protein kinase (NCLK) (Chen et al. 1999), and also formaldehyde markedly induced Tau protein dysfunction and aggregation (Hua and He 2002). We carried out studies on the associations between dysmetabolism of formaldehyde and cognitive impairment (Lu et al. 2011; Lu J et al. 2013a; Lu Y et al. 2013b; He et al. 2016; Su et al. 2016), as well as imbalance in intestinal microbe flora (Liu et al. 2017) and abnormal lysosome (He 2017; Jian and Zhu 2016).

In Chap. 8, we have described that formaldehyde is able to react with protein directly and modify the side chains of lysine, arginine, tryptophan, and cysteine (Rizak et al. 2014), inducing thioflavin S (ThS)-positive Tau aggregates in human neuroblastoma SH-SY5Y cells, and leading to cell death (Nie et al. 2007). In this chapter, among so many potential etiological factors, we would like to discuss how formaldehyde triggers Aβ deposition and Tau hyperphosphorylation because of the following observations: first, formaldehyde is found to be highly produced in vivo and involved in many biological processes; second, levels of formaldehyde are increased with aging in the elderly population (Tong et al. 2013) and correlated with the severity of AD (Tong et al. 2011); and finally, formaldehyde is correlated with formation of plaques and NFTs in the brains of animal models (Lu et al. 2013a, b; Yang et al. 2014a, b).

2 Formaldehyde Triggers Tau Hyperphosphorylation

In 1986, using a combined immunocytochemical and biochemical approach, Grundke-Iqbal et al. demonstrated for the first time that the microtubule-associated protein Tau, a normal brain cytoskeletal protein, was a component of the pared helical filaments (PHFs) (Grundke-Iqbal et al. 1986). A major lesion in AD is the presence of numerous NFTs, which are composed of PHFs (Fig. 10.1). The normal Tau usually carries two to three moles phosphate per mole protein, while PHF-Tau contains six to eight moles of phosphate per mole of the protein (Ksiezak-Reding et al. 1992; Gong et al. 1993). The primary function of Tau is promoting the assembly of microtubules (Weingarten et al. 1975) which will be repressed when Tau is hyperphosphorylated (Lindwall and Cole 1984). Thus, in Tau highly phosphorylated AD brain, disassembly of microtubules was associated with atrophied neurons (Ballard et al. 2011).

Fig. 10.1

Hyperphosphorylated Tau formed tangles in human brain

Human brain sections were obtained and stained with the standard protocols. The phosphorylated Tau protein was represented with pThr181 antibody (green) and tangles were shown in the cells. Nuclei were counterstained with DAPI (blue). (Authors unpublished data)

Phosphorylation and dephosphorylation regulate the function of Tau by decreasing or increasing its affinity of binding to microtubule (Stoothoff and Johnson 2005). Hyperphosphorylation inactivates Tau protein from stabilization of microtubule system and protection of DNA (Lu et al. 2013a, b). Additionally, hyperphosphorylation leads to Tau misfolding and aggregation and sequesters normal Tau, microtubule associated protein 1 and 2, and ubiquitin into PHFs. This insoluble structure damages cytoplasmic structure, interferes with axonal transport, and eventually leads to cell death (Mudher and Lovestone 2002). The hyperphosphorylated Tau composited PHFs will then form NFTs which deposit in the cytoplasm of neurons (Scheuner et al. 1996; Rhein et al. 2009; Tsuji 2010; Alzheimer’s 2015), and impair brain functions of patients suffering from AD (Bird 1993) or other neurodegenerative diseases (Engelborghs and De Deyn 2001; Wu et al. 2012). Therefore, when formaldehyde induced hyperphosphorylation and aggregation of Tau in brains, the above pathological features might occur. It may increase formaldehyde a major problem to a number of neurodegenerative diseases including AD and primary open-angle glaucoma (one of the neurodegenerative disorders) (Cui et al. 2016).

2.1 Tau Hyperphosphorylation in N2a Cells in the Presence of Formaldehyde

As an endogenous metabolite, formaldehyde at physiological concentrations around 0.01 mM was found to promote cell proliferation (Miao et al. 2013). On the other hand, when the formaldehyde concentration increased up to 0.1 mM, cell apoptosis and retardation of cell cycle at S-phase were observed (Miao et al. 2013). Note, it was demonstrated formaldehyde toxicity is correlated to the cell inoculation sizes. The larger the inoculation size, the higher formaldehyde concentrations were needed to decrease the cell viability (Lu et al. 2011). The LD₅₀ of formaldehyde to N2a cells with different inoculation sizes is shown in Table 10.1. Cell process atrophies were observed in the presence of formaldehyde comparing with control (Lu et al. 2011). Similar results were also detected in primary cultured hippocampal neurons incubated with formaldehyde, where the morphological changes of cells indicated that the cellular skeleton/structure was affected by formaldehyde during the treatment (Yu et al. 2014).

Table 10.1

LD50 of FA on N2a cells at different inoculation densities

Time (h)

LD50 (mM)

Inoculum density (cells/mL)

1×10^5

2×10^5

5×10^5

12

0.43

0.55

1.21

24

0.19

0.41

0.85

48

0.15

0.32

0.65

Since the microtubule system plays a critical role in neuronal activities, Lu et al. investigated Tau phosphorylation in N2a cells with formaldehyde treatment (Fig. 10.2) (Lu et al. 2011). Tau hyperphosphorylation was dramatically increased after overloading of formaldehyde (strongest at 2–8 h), and the cell processes shrank along with Tau phosphorylation (Lu et al. 2013a, b). Phosphorylation of Tau protein at sites of Thr181 and Ser396 were detected by Western blotting under the same experimental conditions. The phosphorylation of Tau at Thr181 and Ser396 was also observed with immunocytofluoresence, and the phosphorylation occurred not only in cytoplasm but also in nucleus. Further examination indicated that phosphorylated Tau in nucleus was not overlapping with DNA stained with Hochest-33258. Notably, the phosphorylation level of Tau was decreased after 8 h of formaldehyde treatment, accompanying with regrowth of cell processes. These data manifested that overload of formaldehyde led to Tau hyperphosphorylation, and subsequently severe process atrophies and possibly DNA damage.

Fig. 10.2

Signals of phosphorylated Tau (pThr181 and pSer396) and total Tau (Tau5) after cells were treated with formaldehyde

Phosphorylated Tau was detected by anti-pThr181 and anti-pSer396 antibodies, and total Tau was assayed with Tau5 antibody after cells were treated with formaldehyde for 4 h. Nuclei and F-actin were stained with Hoechst-33258 (blue) and phalloidin (green), respectively. The signals of anti-pThr181 and anti-pSer396 strikingly increased in nuclei of N2a cells, and most of them were rarely co-localized with the DNA staining. A small part of Tau5 signals were co-localized with DNA (Lu et al. 2011)

Polymerization of hyperphosphorylated Tau is a key feature in Tauopathies (Namzaric—a combination of 2 old drugs for Alzheimer’s disease 2015; Lu et al. 2018). Lu et al. examined polymers inside N2a cells using ThS staining and Western blotting. Based on their results, Tau polymer bands with higher apparent molecular masses (~170 kDa for pThr181 and ~130 kDa for pSer396) were observed 2–4 h after the onset of formaldehyde incubation (Lu et al. 2013a, b). The polymers disappeared 8 h after formaldehyde treatment, illustrating that these polymers were reversible. Tau polymerization occurred in synchrony with its hyperphosphorylation and these Tau polymers were shown to be ThS-positive. These data suggested that the polymers should be hyperphosphorylated Tau as they are co-localized with phosphorylation staining and reversible. The reason is, the cross-linked polymers by formaldehyde is hard to disassemble and a higher concentration of formaldehyde is required to perform the cross-link (Luo and He 1999).

Using high-performance liquid chromatography measurement, Lu et al. observed that formaldehyde concentration decreased from 0.5 mM to around 0.1 mM at 8 h and around 0.02 mM at 24 h in the medium with cell cultures, while the concentration only declined to 0.45 mM at 24 h in the cell-free medium (Lu et al. 2013a, b). This experiment demonstrated that the cells metabolized excess formaldehyde. During the formaldehyde incubation, Tau hyperphosphorylation progressed in both concentration-dependent and time-dependent manners. As hyperphosphorylation of Tau leads to microtubule system disruption according to many previous reports (Alonso et al. 2016), this presumably explained the atrophy of cellular processes and neurites observed under formaldehyde treatment. In order to further determine the roles formaldehyde played in Tau protein functionality in vivo, formaldehyde was administrated to mouse as shown in the following paragraph.

2.2 Tau Hyperphosphorylation in Mouse Brain Administrated with Methanol/Formaldehyde

Short-term formaldehyde administration was shown to damage the cognition abilities in both mouse and rat (Lu et al. 2008; Tang et al. 2013). In order to investigate the long-term toxicity of industrial alcohol which contains additional methanol, Yang et al. fed mice (male, ICR) with methanol through drinking water with concentrations of 0%, 2%, and 3.8% over a 6-week period. Their results showed that the spatial recognition and olfactory memory were impaired in the methanol-fed mice through Y-maze and olfactory memory paradigms (Yang et al. 2014a). Meanwhile, pathogenically examination showed that Tau hyperphosphorylation and neuronal death were observed in the hippocampus of those mice. In addition, the severity of those impairments was correlated with doses of methanol given. The methanol-fed model is based on formaldehyde acting as the intermediate product of methanol metabolism. In addition, formaldehyde is an irritated chemical reagent and mice do not like to drink the solution directly.

To further study the effect of formaldehyde on Tau hyperphosphorylation, formaldehyde was directly injected through the tail vein, and hippocampus and cortex of mouse brains were sampled. During this treatment, the fluorescent signal for Tau hyperphosphorylation appeared and lasted much longer up to 7 days than that in N2a cells for 24 h (Lu et al. 2013a, b). Likewise, the phosphorylation of Tau was not only observed in the cytoplasm, but also in the nuclei. The phosphorylated Tau was not overlapped with DNA staining in the nuclei, similar to the results in N2a cells (Lu et al. 2011). Liu et al. allowed C57BL/6 mice to be exposed daily to formaldehyde (1.55 and 15.5 mg/kg/day) in the air for 1 week. Pathological alterations occurred in the mouse brain including cognitive deficits and accumulation of hyperphosphorylated Tau in the cerebral cortex after the acute formaldehyde exposure (Liu et al. 2018). These data indicate formaldehyde is able to induce Tau hyperphosphorylation in the animal brain in spite of different exposure manners.

Phosphorylation at sites Thr181 and Ser396 of Tau protein was detected in the brain of mice and Macaca mulatta in the administration of formaldehyde or methanol (Lu et al. 2011, 2013a, b; Yang et al. 2014b). As described by Zhai et al. (2018), levels of pTau181 were markedly higher in the hippocampus and prefrontal cortex of young rhesus macaques compared with control group by chronic intracerebroventricular (i.c.v.) injections of formaldehyde. Tau epitopes, such as Thr181 and Ser396, are sensitive to phosphorylation (Gong et al. 2005; Li and Paudel 2006). Specifically, studies have shown that Tau phosphorylated at sites such as Thr181, Thr231, and Ser396 may initiate early pathological changes in Tau by disrupting proper Tau localization, initiating Tau oligomerization, and facilitating Tau accumulation and extracellular export (Carroll et al. 2021). Hyperphosphorylation of Thr181 in the CSF is employed as a biomarker to predict AD (Blennow 2005; Olsson et al. 2005). According to Tsiknia et al., higher plasma pThr181 levels in women were associated with more cortical Aβ deposition, higher concentrations of pThr181 in CSF, more entorhinal cortical Tau deposition, and lower brain glucose metabolism than in men (Tsiknia et al. 2022). It suggests that plasma pThr181 and pThr231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with Lewy bodies (Gonzalez et al. 2022). Thr181, Aβ, and glial fibrillary acidic protein (GFAP) can predict risk of clinical Alzheimer’s disease diagnosis within 17 years (Beyer et al. 2023). Formaldehyde concentration was higher in the CSF of AD patients compared to control provided by Beijing Hospital of Elderly (our unpublished data). Some studies showed phosphorylated-Ser396/Ser404-Tau in axonal lesions of the white matter and in the neuropil (Aragao Gomes et al. 2021). Using compound 24r, a potently inhibitor of AChE, Liu et al. reduced Tau phosphorylation at Ser396 residue, providing neuroprotection by rescuing neuronal morphology and increasing cell viability (Liu et al. 2022). Hyperphosphorylation of Ser396 results in decreased Tau solubility and is believed to be a crucial step in the development of a neurofibrillary pathology in AD patients’ brain (Michel et al. 1998; Abraha et al. 2000). In fact, to clarify the relationship between formaldehyde and Tau phosphorylation involved in age-related cognitive impairment, more phosphorylation sites should be detected to support formaldehyde-related dementia in the aging population, although Thr181 and Ser396 are found critical in the brain of Alzheimer’s patients.

2.3 Tau Hyperphosphorylation in Monkey Brain Administrated with Formaldehyde

Though Tau hyperphosphorylation was detected in mouse brain by administration of methanol/formaldehyde, degradation of formaldehyde is much more efficient in mouse than in human beings. Excess methanol is seriously toxic to primates, leading to severe lesions to eye and neural cells where methanol end metabolite formic acid accumulated (MacAllister et al. 2011). Rodents, however, are able to syntheses enough folate to degrade formic acid so that methanol-induced brain damages are compromised in rodents (Bruckner and Warren 2001). Further cytotoxicity test using mouse primary neurons with methanol, formaldehyde and formic acid, showed that formaldehyde was the most toxic with the least neurites and highest Tau phosphorylation levels (Yang et al. 2014a, b). On the other hand, Alzheimer’s disease develops in a chronic pathological way, thus a long-term trial should be carried out to simulate the disease. To determine the role of formaldehyde, an intermediate metabolite in methanol degradation in (AD) pathology, Yang et al. provided an impetus to investigate the chronic effects of methanol exposure by feeding methanol, the precursor of formaldehyde. They employed rhesus macaque to establish a non-human primate model in age-related cognitive impairment through a chronic feeding of young male monkeys with 3% methanol ad libitum (Yang et al. 2014a, b). As a small molecule, formaldehyde can freely pass the blood–brain barrier (Shcherbakova et al. 1986).

Cognitive ability (working memory) of monkeys was assessed with a variable spatial delayed response task (VSDRT) as used previously (Arnsten et al. 1988; Wang et al. 2013a, b). As the task results showed, a long-term of methanol feeding leads to persistent memory impairment in the monkeys. The working memory impairment lasted at least 6 months beyond the feeding regimen, suggesting a permanent-like cognitive impairment for the employed monkeys. The cognitive impairment was coincided with the increase in Tau phosphorylation at residues of Thr181 and Ser396 in CSF during the feeding. Distinct increases in Tau phosphorylated aggregates (some of them look like NFTs) were also observed in four brain regions postmortem: frontal lobe, parietal lobe, temporal lobe, and hippocampus (Yang et al. 2014a, b). Tau hyperphosphorylation in the brain maintained and persisted even 6 months after feed of methanol ceased. That is to say, methanol feeding caused long-lasting and persistent pathological changes that were related to AD-like behavior in monkeys. In addition, levels of phosphorylated Tau in CSF depended on doses of methanol fed.

3 Enzymes Involving Tau Phosphorylation in the Presence of Formaldehyde

3.1 Activation of GSK-3β in the Presence of Formaldehyde

As mentioned above, Tau was phosphorylated at Thr181 and Ser396 under formaldehyde treatment both in nucleus and cytoplasm. So far, more than 20 kinases are involved in Tau phosphorylation (Wang et al. 2013b). Glycogen synthase kinase 3 beta (GSK-3β) catalyzes more than 11 phosphorylation sites on Tau protein including Thr181 which was significant in formaldehyde-induced Tau hyperphosphorylation. The phosphorylation of Tyr216, which signified the activation of GSK-3β, was markedly elevated in N2a cells in the presence of formaldehyde (He et al. 2016). Furthermore, GSK-3β was found to be increased in the nucleus with the addition of formaldehyde which might contribute to the phosphorylation of nuclear Tau (Lu et al. 2013a, b). On the other hand, formaldehyde-induced Tau phosphorylation was greatly reduced when activation of GSK-3β was inhibited by its inhibitor LiCl or siRNA targeting to GSK-3β. In fact, GSK-3β is regarded as one of the most important kinases to produce hyperphosphorylation of Tau in AD (Jembrek et al. 2013). Intracellular accumulation of Aβ also likely induces increase in hyperphosphorylated Tau by a mechanism dependent on GSK-3β (Alvarez et al. 1999). Other kinases such as cyclin-dependent kinase 5 (CDK5), EARK1/2, 14-3-3ε were also tested; none showed strong effect as GSK-3β. Thus, these experiments indicated formaldehyde can activate GSK-3β and further lead to Tau multiple phosphorylation and aggregation in vitro and in vivo (Lu et al. 2013a, b).

3.2 Activation of CaMKII in the Presence of Formaldehyde

Calmodulin-dependent protein kinase II (CaMKII) is reported to participate in Tau phosphorylation (Wang et al. 2013a, b). It is a remarkably complex protein kinase, involving synaptic plasticity and memory formation. Dysregulation of CaMKII may thus be a trigger of pathology in AD, a dementia characterized by aberrant calcium signaling, synapse and neuronal loss, and impaired memory (Ghosh and Giese 2015). CaMKII prefers to phosphorylate Tau at Ser396 and six other residues (Wang et al. 2013a, b). Thus, He et al. determined expression levels of CaMKII in N2a cells which were incubated with formaldehyde. They observed upregulation of CaMKII protein levels induced by formaldehyde (He et al. 2016). That is to say, the activation of CaMKII may contribute to Tau phosphorylation at Ser396, too. CaMKII dysregulation critically contributes to neurodegeneration and memory impairment in AD (Sanhueza and Lisman 2013).

As described by Sanhueza and Lisman, synaptic strength is stored stably through the combined actions of the CaMKII/NMDAR (N-methyl-D-aspartate receptor) complex and N-cadherin dimers (Sanhueza and Lisman 2013). Storage of synaptic information may instead be mediated by regulated interaction of CaMKII with NMDAR complex. Recent findings also implicated roles of CaMKII in long-term depression (LTD), as well as functional roles at inhibitory synapses (Coultrap and Bayer 2012). Tong et al. found that elevation of formaldehyde markedly suppressed LTP in rat hippocampus (Tong et al. 2011). As their Western blotting results showed, formaldehyde also induced downregulation of NMDA receptors, such as NMDAR subtype 2B (NR2B) and NMDAR subtype 1 (NR1), in a concentration-dependent manner (Tong et al. 2013). Thus, it appears that upregulation of CaMKII in N2a cells may be due to the suppression of NMDA receptors in the presence of formaldehyde.

3.3 Changes of Dyrk1A and CDK5 in the Presence of Formaldehyde

Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) phosphorylates 11 sites on Tau including Thr181 and Ser396 (Liu et al. 2008; Wang et al. 2013a, b). According to Lu et al., expression of Dyrk1A, however, decreased in N2a cells during formaldehyde stress (Lu et al. 2013a, b). That is to say, Dyrk1A did not participate the phosphorylation of Tau in the presence of formaldehyde. Cyclin-dependent kinase 5 (CDK5) functioning with its coactivator p35 and truncated coactivator p25 (p35/p25) phosphorylates Tau protein at multiple sites including Thr181 and Ser396 (Tsai et al. 1994; Patrick et al. 1999; Kesavapany et al. 2004; Wang et al. 2013a, b). Compared with the control group, formaldehyde caused no significant increase in levels of p35/p25 or transcription of CDK5 in N2a cells under the same experimental conditions (Lu et al. 2013a, b).

3.4 Downregulation of PP2A in the Presence of Formaldehyde

Phosphoseryl/phosphothreonyl protein phosphatase-2A (PP2A) is a large family of enzymes that account for the majority Ser/Thr phosphatase activity in brain (Wang et al. 2013a, b). Dysfunction of PP2A is closely related to Tau hyperphosphorylation, amyloidogenesis, and synaptic deficits. It is a particularly interesting field to study changes in PP2A catalytic activities, regulators of PP2A, expressions of its subunits, methylation, and/or phosphorylation modifications in AD-affected brain regions. Deregulation of PP2A affects activity of many Ser/Thr protein kinases implicated in AD (Sontag and Sontag 2014). However, it remains unclear what are the primary events underlying “PP2A“dysfunction in AD. He et al. incubated N2a cells with formaldehyde and found that the levels of PP2A protein markedly decreased. However, the decrease in PP2A could be rescued by addition of resveratrol to N2a cells (He et al. 2016).

According to Chan and Sucher, stimulation of NMDARs led to dissociation of PP2A from the complex and reduction of PP2A activity. They believed that NMDARs were allosteric modulators of PP2A, which in turn controlled their own phosphorylation state (Chan and Sucher 2001). Comparing previous work reported by Tong et al., it suggested that the suppression of PP2A of N2a cells in the presence of formaldehyde was due to inactivation and downregulation of NMDARs (Tong et al. 2015; He et al. 2016).

4 Tau Hyperphosphorylation and DNA Damage

Tau protein is also located in the nucleus of cell, although it is mainly known as an axonal microtubule-associated protein (Loomis et al. 1990; Wang et al. 1993; Lu et al. 2014). As described, neuronal tau was observed to be able to bind to DNA and increase its melting temperature (Hua and He 2000). Bound to DNA, Tau protect DNA and prevented DNA from attacks by free radicals (Hua and He 2002, 2003; Hua et al. 2003). Tau protein and DNA complex displayed a beads-on-string like structure (Hua and He 2003). The beads were composed of Tau and folded DNA called DNA-Tauosome (Lu et al. 2013a, b). Tau protein can be stained with immunofluorescence only in human cells such as SH-SY5Y. However, when applied with subcellular fractionation or nuclei isolation method, Tau was able to detect in rodent nucleus, too (Lu et al. 2014). Nuclear Tau is usually hypophosphorylated, which means the phosphorylation may also regulate the transportation of Tau across the nuclear envelope (Sultan et al. 2011). Hyperphosphorylation promoted Tau to separate from not only microtubules but also double-stranded DNA. Thus, the DNA-Tauosome will be disrupted when the bound Tau protein was dissociated from the complex (Lu et al. 2011). Formaldehyde induces tau aggregation leading to loss of its ability of binding to DNA (Hua and He 2002). As mentioned above, formaldehyde triggers Tau hyperphosphorylation in neural cells (Lu et al. 2013a, b; Yang et al. 2014a, b). Therefore, DNA could be damaged after the loss of protection by Tau protein when Tau is hyperphosphorylated in the presence of formaldehyde.

5 Tau Phosphorylation and Accumulation at the Pathological Concentration of Formaldehyde

In fact, age-related cognitive impairment is a chronic and relentless progression. A chronic exposure to formaldehyde, which can cross the blood–brain barrier freely (Shcherbakova et al. 1986), leads to impairment of human memory (Kilburn 1994; Tong et al. 2013). The average pathological concentration of formaldehyde in the urine of AD patients is 13.70 ± 5.17 μM, which is ~1.4 times as high as that of the physiological formaldehyde concentration (9.61 ± 2.90 μM) from age-matched normal participants (Li et al. 2016). However, concentrations of formaldehyde used in previous reports were much higher than concentrations of endogenous formaldehyde in aging people under either physiological or pathological states. Therefore, long-term cellular effects of exposure to low concentrations of formaldehyde, which is consistent with pathological concentration, should be investigated. The concentration of formaldehyde used to treat cells was based on the average levels of endogenous formaldehyde in AD patients, and the level of formaldehyde in age-matched normal aging participants was used as control. The experimental process attempted to clarify whether formaldehyde at as low as the pathological concentration affects the morphology and connectivity of neurons.

Wang et al. established a cell culture system with a long-term treatment with formaldehyde to simulate the chronic exposure to pathological concentration of formaldehyde. This experimental protocol was to clarify whether low concentration and long-term exposure can cause formaldehyde accumulation in cells (Wang et al. 2017). The answer was positive. The response of N2a cells to the low concentration formaldehyde exposure was examined (Wang et al. 2017). They found that the pathological concentration of formaldehyde decreased cell viability, altered cell morphology, and increased Tau hyperphosphorylation. They also monitored the changes of cellular morphology using digital holographic microscopy after a 6-day incubation with formaldehyde. As shown in Fig. 10.3, changes in the morphological indexes can be observed, which could directly reflect the effect of formaldehyde accumulation on cell growth, cell adhesion, and the spreading of cell processes (Wang et al. 2017). They adjusted thickness value to exclude interference of dimension of cell volume on cell thickness, making it more reliable for describing the adhesive capacity of cells. After a long-term treatment with pathological level of formaldehyde, cells became rounder, less attached to the bottom of the culture dish and fewer cell processes compared with the control cells. To demonstrate the effect of formaldehyde accumulation (Fig. 10.4), they also performed the primary culture of hippocampal neurons from mouse and observed the decreases in neurites under the same experimental conditions (Wang et al. 2017). These results suggested that low concentration of formaldehyde accumulation chronically suppresses the connections among neurons in culture.

Fig. 10.3

Morphological changes of N2a cells in the presence of formaldehyde

Cell culture and inoculation were performed as described for Fig. 10.2. Aliquots of N2a cells were taken daily for the measurements of their morphologies on a holographic imaging system (Phase Holographic Imaging AB, Sweden) in order to analyze the thickness/^volume (panel a), average area (panel b), and average volume (panel c) at 4 h, when N2a cells were adherent. Values are expressed as the means ± SEM; *P < 0.05, **P < 0.01,***P < 0.001 versus the control group; ##P < 0.01, ###P < 0.001 versus the control group on the first day. The P values were obtained based on comparative analysis of the indicated group with the controls. Inverted phase-contrast microscopy showed the morphology of N2a cells in the presence (panel d) or absence (panel e) of formaldehyde on day 5 (Wang et al. 2017)

Fig. 10.4

Changes in neurites in the presence of formaldehyde accumulation

The representative morphology of the neurites of primary hippocampal neurons cultured in the presence of 10 μM formaldehyde (panel a) and control neurons cultured without the presence of formaldehyde (panel b) were displayed. The primary neurons were transfected with EGFP plasmid at 13 days in vitro and the transfected neurons were then treated with FA at the concentration of 10 μM for 3 days. The medium was changed every day. Images of EGFP-positive neurons were observed with fluorescence confocal microscopy. Scale bar = 10 μm. The number of primary neurites was quantified by the ImageJ software. The number of primary neurites of the FA-treated neurons (n = 53) was significantly smaller than the control neurons (n = 64). (d) The distribution of primary neurites numbers in the FA-treated and control neuron populations differed significantly. The distribution of neurites number was analyzed by Chi-square test. Data in (panel c & d) were collected from three independent experiments. Data are shown as mean ± SEM. Means were compared with one-way ANOVA. *P < 0.05; **P < 0.01 (Wang et al. 2017)

The cytoskeletal system, for instance, the microtubule system, is essential to maintain cellular morphology. As a microtubule-associated protein, Tau functions in the promotion and stabilization of the microtubule system and actin filaments (Weingarten et al. 1975; Drubin and Kirschner 1986; Avila et al. 2006), and it is regulated by phosphorylation and dephosphorylation (Caceres and Kosik 1990). When Tau is hyperphosphorylated, Tau disassociates from microtubules or actin filaments, followed by the disruption of the cytoskeleton. In other words, Tau hyperphosphorylation causes the disruption of cellular processes, especially the terminal processes. Tau was markedly phosphorylated during the long-term treatment with low concentration of formaldehyde, followed by cell shrinkage and even cell death. Tau hyperphosphorylation should be one of the explanations for the distinct change of cellular morphologies in the presence of low concentration of formaldehyde. Probably, formaldehyde exposure induces cell stress and may impair cellular and nuclear transport (Dubey et al. 2023). Alzheimer’s disease is characterized by an almost complete redistribution of Tau protein pool from microtubule-bound to an aggregated state in the form of pathological amorphous oligomers and PHFs (Goedert et al. 1988; Harrington et al. 1991). Tau hyperphosphorylation usually occurred at early stage in the process of neurofibrillary degeneration of AD, and positively correlated with progression and diagnosis of dementia in AD patients (Kopke et al. 1993). In other words, incubation with pathological concentrations of formaldehyde induced chronic damages to N2a cells and primary cultured murine hippocampal cells, including the atrophy of neurites resulted from Tau hyperphosphorylation.

6 Aβ Deposition in the Presence of Formaldehyde

Amyloid β peptides are critically involved in AD as the main component of senile plaques found in the brains of Alzheimer’s patient. The amyloid precursor protein (APP) is cleaved by γ secretase and β secretase to yield Aβ (Shu et al. 2015). A large body of literatures reported that vascular disorders are involved in the pathogenesis of vascular dementia and AD (Wallin et al. 2016a, b). In 2001, Yu hypothesized that SSAO-mediated generation of formaldehyde can induce protein Aβ1–40 cross-linkage, deposition, and subsequently plaque formation in the compartment adjacent to the cerebral vessels (Yu 2001). As described, SSAO-mediated deamination of methylamine or aminoacetone produces toxic formaldehyde and methylglyoxal, respectively (Yu 2001). These aldehydes can cause intramolecular and intermolecular protein cross-linkages. As Chen et al. have reported, aldehydes such as formaldehyde, methylglyoxal and malondialdehyde at low concentrations accelerated the formation of β-amyloid, β-sheets, oligomers, and protofibrils as well as increased sizes of the aggregates (Chen et al. 2007). So far, we believed that imbalance of formaldehyde metabolism, originated from many metabolic pathways, is one of the risk factors to age-related cognitive impairment (He et al. 2010). Sun et al. observed that treatment on human neuroblastoma cells with geniposide, a traditional Chinese drug, resisted to Aβ aggregation induced by formaldehyde (Sun et al. 2013).

Monkeys display similar hallmarks of neurodegeneration and aging as humans, for instance, senile plaque formation in their brain (Beckman et al. 2019; Paspalas et al. 2018). To demonstrate whether formaldehyde is able to induce amyloid plaques in vivo, Yang et al. have studied the brain of monkey which was fed with methanol as described above (Yang et al. 2014a, b). Methanol is converted to formaldehyde in vivo. In their observations, senile plaques were found in four brain regions postmortem: frontal lobe, parietal lobe, temporal lobe, and hippocampus. It seems as if formaldehyde induced Aβ deposition by the activation of β- and γ-secretase. The presence of amyloid plaques in monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defense in mouse against methanol toxicity makes it unable to completely mimic AD pathology.

In order to reveal formaldehyde but not methanol leading to AD-like changes, Zhai et al. (2018) monitored changes in cognitive ability of monkeys treated with formaldehyde and evaluated common AD pathological markers in the postmortem. They employed young Rhesus macaques (5–8 yrs) and performed chronic intracerebroventricular (i.c.v.) injections of formaldehyde or vehicle to the monkeys for over a year. Monkeys receiving the injections (i.c.v.) of formaldehyde significantly suffered from spatial working memory decline, following AD-like pathological characteristics such as Aβ loaded neuritic-like plaques, Tau hyperphosphorylation in NFT-like formations, neuronal loss and reactive gliosis in entorhinal cortex, hippocampus and prefrontal cortex (PFC), where Aβ42 and pT181 levels were markedly high (Zhai et al. 2018).

To exclude the side effect of the injections (i.c.v.) inducing some artificial changes, Li et al. (2020) recruited 56 rhesus monkeys (aged from 4 to 26 years) without any additional treatments such as injections, and measured levels of Aβ40, Aβ42, and formaldehyde in the CSF. They observed a significant decrease in the levels of Aβ40 and Aβ42, following an increase in formaldehyde with age. Except for young and middle-aged monkeys, levels of formaldehyde were negatively correlated with those of Aβ40 and Aβ42 in CSF of aged ones, similar to parallel changes that decreased Aβ in CSF is associated with increased formaldehyde in AD patients and normal aged adults. That is to say, changes in Aβ are associated with formaldehyde concentrations in the CSF of rhesus monkeys as aging. These results not only indicate that rhesus monkey is a good animal model for studying AD, but also suggest that formaldehyde may be the diagnostic indicator and an important factor in AD development.

7 Aggregation of ApoE4 in the Presence of Formaldehyde

In humans, there are three variant alleles at the APOE locus: ε2, ε3, and ε4. In 2009, it was found that carrying the Alzheimer risk variant ApoE4 is associated with an accelerated decline in memory function in midlife, according a 15-year longitudinal study (Reiman et al. 2009). ApoE4 is the most risk factor in the development of late-onset AD (LOAD) (Huang et al. 2004a, b; Castellano et al. 2011). Apolipoprotein E is an essential cholesterol carrier in brain and helps in neuronal maintenance and repair. People who develop AD are more likely to have an APOE ε4 allele than people who do not develop the disease. About 25% of people carry one copy of ApoE4, and 2–3% carry two copies. ApoE4 is the strongest risk factor gene for Alzheimer’s disease, although inheriting ApoE does not mean a person will definitely develop the disease (Matters 2021). ApoE4 could increase a person’s chances of developing the neurodegenerative disease by up to 12-folds. A recent study showed that the presence of ApoE4 exacerbates the brain damage caused by toxic tangles formed by Alzheimer’s-associated Tau protein. In the absence of ApoE, Tau tangles did very little harm to brain cells. Blocking ApoE4 in brain may prevent nerve cell death, inflammation (Shi et al. 2017).

In 2014, Hu et al. observed that ApoE4, the isoform with arginine residues at 112 and 158, forms aggregates with more APOE (P < 0.05) and Aβ (P < 0.001) in formaldehyde solution (10 mM) than that formed with either ApoE3 or ApoE2 protein. These data suggested the trend of vulnerability conferred by the APOE genetic variations (ApoE4 > ApoE3 > ApoE2), appearing that formaldehyde may play a role in the differential patterns of amyloid plaque formation in people with differing APOE genetic backgrounds (Rizak et al. 2014). Levels of urinary formaldehyde and formic acid often changed dynamically related to the deterioration of cognitive ability (Liu et al. 2023; Chen et al. 2023). To clarify the relationship between ApoE4 and endogenous formaldehyde, Wang et al. recruited participants that 136 with AD dementia, 171 with mild cognitive impairment (MCI), 140 with objectively defined subtle cognitive decline (Obj-SCD), 110 with subjective cognitive decline (SCD), and 72 with cognitively normal controls (NC). Urinary formaldehyde levels were related to APOE ε4 genotype and the presence of Aβ depositions in the brain (Wang et al. 2022). In addition, after excluding the influence of covariates, urine formaldehyde concentration showed significant independent correlation with gender, plasma Aβ42, and pThr181 (Wang et al. 2022). Levels of formic acid and formaldehyde in urine may not only be used for differentiation between AD and cognitively normal control, but also may improve the prediction accuracy of plasma biomarkers for cognitive impairment stages of AD. This discovery will not only allow for large-scale preliminary screening and early diagnosis in population, but also help selection of suitable enrollees with a high risk of developing AD before onset for future clinical trials.

8 Formaldehyde Induces Tau Hyperphosphorylation from Olfactory System

Olfaction involves different processes from sensory neurons to the OB, including decoding and plasticity of the prefrontal cortex, and finally the downstream neurons in the hippocampus (Brennan and Keverne 1997). Olfactory system is a unique brain in neurodegenerative disease (Hawkes 2003), which has a high opportunity to be exposed to formaldehyde in the air. Neuropathological studies showed that the underlying causes of AD olfactory dysfunction are related to the presence of NFTs (Li et al. 2021). Hyperphosphorylated tau in olfactory bulb may reflect the severity of AD pathology in other brain regions (Attams et al. 2014). As shown in an animal experiment, indoor formaldehyde exposure daily in the air induces Tau hyperphosphorylation and Aβ deposition in the brain of C57BL/6 mice, which is considered as early AD-like changes (Liu et al. 2018). Olfactory dysfunction is regarded as an early potential biomarker for the AD diagnosis (Wesson et al. 2010). Hyperphosphorylated Tau and NFTs occur in medial temporal lobe (MTL) at early stage of AD and then spread to other regions of patients’ brain (Busche and Hyman 2020). Formaldehyde induced AD-like pathologies and cognitive impairments in mice and non-human primates (Lu et al. 2013a, b; Zhai et al. 2018). As a hypothesis here, formaldehyde-induced hyperphosphorylated Tau first appears in olfactory system, for instance, olfactory bulb, then spreads to MTL including entorhinal cortex, hippocampus, and parahippocampus, and to cortex during the AD progression (Fig. 10.5).

Fig. 10.5

A putative hypothesis that brain regions where Tau hyperphosphorylation occurs from early to late stage of AD

Formaldehyde (FA)-induced hyperphosphorylation of Tau occurs in olfactory system in the early period of age-related cognitive impairment, then spreads to medial temporal lobe (MTL) including entorhinal cortex, hippocampus and parahippocampus, and further to cortex (Cx) during the progression of AD

9 Conclusion

Formaldehyde acts as an effective trigger of Tau protein hyperphosphorylation in neural cell lines and primary cultured neurons. As shown in the schematic Fig. 10.6, with a short-term formaldehyde treatment, Tau phosphorylation and polymerization occur, followed by dephosphorylation and depolymerization as formaldehyde levels decreased. Maintaining a high level of formaldehyde for a longer period, the Tau hyperphosphorylation lasts even longer and leads to irreversible aggregation and cell death. The activation of GSK-3β and CaMKII as well as suppression of PP2A might be a mechanism underlying formaldehyde-induced Tau pathologies. Cells may respond to overloaded formaldehyde in diverse manners. As clinical investigation shows, urine formaldehyde levels were associated with APOE genotype in NC and AD individuals. In primates experiments, feeding methanol in drinking water and the injection (i.c.v.) of formaldehyde can induce AD-like disorders such as memory decline, Aβ deposition or plaques, Tau hyperphosphorylation and NFT-like changes, as well as gliosis in hippocampus and cerebral cortex, similar to AD-like changes in mice under the same conditions. The measurements of natural aged monkeys demonstrated that concentrations of formaldehyde are associated with changes in amyloid-β in CSF of rhesus monkeys as aging. Aβ deposition in monkey brain may be due to the activation of β- and γ-secretase, but the mechanism of activation needs further investigating. Amyloid β deposition and Tau hyperphosphorylation occur early (preclinical) in age-related cognitive impairment. However, as a potential trigger of Tau phosphorylation, it suggests that the onset of dysmetabolism of endogenous formaldehyde should process before Aβ deposition and Tau phosphorylation in the early onset of preclinical stage of AD.

Fig. 10.6

A putative mechanism for Tau hyperphosphorylation and polymerization and Aβ deposition in the presence of formaldehyde overload. Formaldehyde overload causes activation GSK-3β and CAMKII and nuclear accumulation of GSK-3β, then Tau protein, especially nuclear Tau, becomes highly phosphorylated. Meanwhile, PP2A was inhibited, leading to the accumulation of hyperphosphorylated Tau and subsequent formation of ThS-positive polymers, even PHFs. Hyperphosphorylated Tau in the nucleus may disassociate from DNA and lose its protective function to DNA. Levels of Tau phosphorylation in the cytoplasm increase and reduce the ability of Tau protein to bind to microtubules, resulting in destabilization of microtubules. Formaldehyde leads to the activation of β and γ secretases, increasing the production of Aβ, and secretion of Aβ

Acknowledgement

All grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_11

11. Formaldehyde Exposure Leads to Circadian Rhythm, Anxiety, Depression, and Other Neuropsychiatric Disorders

Xiumei Wang¹, Shirui Huo², Ying Liu², Yan Wei³ and Rongqiao He3  

(1)

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

(2)

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China

(3)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Epidemiological studies have demonstrated that individuals exposed to formaldehyde exhibit a range of neuropsychiatric symptoms, encompassing disturbances in circadian rhythm, disrupted sleep patterns, anxiety, depression, and anorexia. Meta-analyses and bioinformatics methodologies provide compelling evidence and plausible biological explanations for the link between formaldehyde exposure and brain disorders. Except for exogenous exposure, psychiatric disorders may also be associated with endogenous formaldehyde accumulation resulting from impaired metabolism induced by aging or diseases. Elevated exogenous or endogenous formaldehyde level leads to increased concentrations of formaldehyde (or formic acid) in patients’ urine, which can be used as a predictive marker for certain neuropathological conditions. Herein, we propose that the formaldehyde cycle may act as a regulator of circadian rhythm by influencing the metabolism of melatonin (MT), norepinephrine, epinephrine, and serotonin. The S-adenosyl-L-methionine (SAM)/S-adenosyl-L-homocysteine (SAH) ratio shows circadian rhythms, with formaldehyde acting as a donor of methyl group and participating in the methylation of histone, DNA and RNA. We also discuss the impacts of formaldehyde exposure on psychosomatic and neuropathological behaviors, including sleep disturbances, anxiety, depression, and other behavioral disorders, in addition to cognitive impairment.

Keywords

FormaldehydeCircadian rhythmSleepAnxietyDepression

Abbreviations

A

AD

Alzheimer’s disease

ALS

Amyotrophic lateral sclerosis

AChE

Acetylcholinesterase

C

CORT

Corticosterone

CNS

Central nervous system

D

DA

Dopamine

E

EPM

Elevated Plus-Maze tests

F

FA

Formaldehyde

FST

Forced swimming tests

G

GRs

Glucocorticoid receptors

H

HPA

Hypothalamo-pituitary-adrenal gland

I

IARC

International Agency for Research on Cancer

M

MT

Melatonin

N

NAS

N-acetylserotonin

NLMS

National Longitudinal Mortality Study

O

OFT

Open-field tests

P

ppm

Parts per million

S

SAH

S-adenosyl-L-homocysteine

SAM

S-adenosyl-L-methionine

SBS

Sick building syndrome

SNAP25

Synaptosomal-associated protein 25

T

TH

Tyrosine hydroxylase

TRP

Transient receptor potential channels

TRPA1

Transient receptor potential cation channel subfamily A member 1

TUR

Toxics use reduction

1 Introduction

Exogenous formaldehyde is omnipresent and infiltrates the human body via various ways including inhalation through the respiratory tract, dermal absorption through the skin, and ingestion through food. Its high water solubility and reactivity facilitate its absorption predominantly in the upper airways, accounting for over 90% of airborne formaldehyde absorption (Nielsen et al. 2013). Chronic, low-level exposure to formaldehyde generally triggers respiratory disturbances such as rhinitis and anaphylaxis, along with detrimental effects on neurological, dermatological, gastrointestinal, musculoskeletal, cardiac, and endocrinological systems (Gibson and Vogel 2009). Heightened exposure poses a significant risk for the development of tumors and cancers in the upper respiratory tract (Kilburn et al. 1985a) and leukemia (Cogliano et al. 2005). The International Agency for Research on Cancer (IARC) has unequivocally concluded that: “there is sufficient evidence in humans for the carcinogenicity of formaldehyde. Formaldehyde causes cancers of the nasopharynx and leukemia” (IARC 2012). Moreover, through meta-analysis and bioinformatics methodologies, Rana et al. (2021) emphasized a correlation between formaldehyde exposure and brain disorder. Spatial–temporal variations in tropospheric formaldehyde levels correspond with the geographical distribution of formaldehyde-induced Alzheimer’s disease (AD) among older adults (aged 60–89) of both genders (Yuan et al. 2023). In general, indoor formaldehyde levels exceed outdoor concentrations due to multiple indoor sources and limited air exchange rates. Persistent impairments and symptoms in central nervous system (CNS) have been reported in occupationally or nonoccupationally formaldehyde-exposed individuals (Sparks et al. 1990; Lu et al. 2008; Kim et al. 2015). Work-related formaldehyde exposure has been linked to headaches, panic, anxiety, depression, fatigue, sleep disturbances, decreased cognitive, and memory dysfunctions (Kilburn et al. 1987). Similarly, formaldehyde exposure adversely impacts murine behavior and cognitive abilities, mimicking symptoms observed in humans (Bhatt and Panchal 1992; Aslan et al. 2006; Li et al. 2016a).

Barring accidents, the risk of high-concentration formaldehyde exposure in the workplace is generally mitigated due to the implementation of protective measures in occupational settings where formaldehyde is present. However, formaldehyde resin-containing materials are widely used in home decoration, leading to prolonged low-level indoor exposure for many individuals. Patients with melatonin (MT) deficiency often report cognitive issues, which can be further exacerbated by formaldehyde exposure (Mei et al. 2016). Additionally, age-related cognitive impairment, often accompanied by neuropsychiatric disorders such as sleep disturbances, depression, anxiety, and aggression, may deteriorate with formaldehyde exposure. To prevent formaldehyde-induced cell dysfunction that can cause substantive organ damage and even carcinogenesis, it is crucial to minimize exposure and adopt effective protective measures.

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) share some common neuropsychiatric symptoms, and experimental data and bioinformatics approaches provide compelling evidences for the association between formaldehyde exposure and these brain diseases (Li et al. 2020a, b; Fei et al. 2021; Rana et al. 2021). Formaldehyde toxicity has been implicated in the development of age-related neurological dementia and other brain disorders (Kou et al. 2022), as we have reviewed cognitive dysfunction and formaldehyde in Chap. 9. Mental disorders constitute another crucial area of research that warrants attention (Hu et al. 2016). In this discussion, we will focus on the impact of formaldehyde exposure on psychosomatic behaviors, including disruptions in biological rhythm, depression, anxiety, and other behavioral disorders, beyond cognitive impairment.

2 Formaldehyde and Circadian Rhythm

2.1 Formaldehyde Exposure Disturbing Sleep Patterns

Circadian rhythms regulate vital processes like sleep, body temperature, metabolism, and endocrine secretion, enabling organisms to synchronize with daily environmental fluctuations. It is well-documented that Alzheimer’s patients suffer from disrupted circadian rhythm (Bocksberger 1977; Hiller and Ishii 2018). Disturbances in these rhythms, including sleep architectures, ingestion, and gut microbiota, may contribute to the pathogenesis for age-related cognitive impairment (Li et al. 2021a, b). To investigate the impact of formaldehyde on sleep and related behaviors, Kilburn et al. (1985a) conducted a study comparing two groups of women: those employed in histological labs with daily exposure to formaldehyde, xylene, and toluene, and unexposed clerical staff working in the same hospital. They compared the disturbances of neurobehaviors such as sleep, memory, mood, and indigestion between two groups, and found that formaldehyde exposure was more strongly correlated with neurobehavioral symptoms, respiratory and mucous membrane symptoms than exposure to xylene/toluene or to other agents (Kilburn et al. 1985a). Weber et al. reported a case involving a family who suffered from sleeping disturbances, malaise, headache, nausea, anorexia, and irritation of upper airway and eye due to chronic formaldehyde exposure in their newly renovated apartment (Weber et al. 1988). These findings underscore the significant impact of formaldehyde on indoor air quality (IAQ). As described by Fritz et al. (2022), formaldehyde, relative humidity (RH), and building ventilation rate are the most influential factors in predicting the perception of IAQ.

Effects of formaldehyde on sleep and pain have been recognized in scientific research for decades. Direct evidence of formaldehyde interfering with the sleep-wake cycle includes studies where the aldehyde was injected into animals to induce pain (Coderre et al. 1984; Park et al. 2011). Zaman et al. (2015) injected formaldehyde into mice to induce paw edema and pain, disrupting their sleep, to evaluate an herbal remedy (Nidrakar bati) with sleep-inducing properties. In another study, Niiro et al. (2021) injected formaldehyde into the trigeminal nerve of rodents to disturb their circadian rhythms and observed that pain in the trigeminal region was more intense during nighttime than during the day. Zhang et al. (2012) proposed a pathway for circadian nociceptive transmission, involving peripheral circadian-regulated signaling, which modulates circadian inflammatory pain induced by formaldehyde, with spinal substance P potentially playing a crucial role.

Compared to controls exposed to air, significant alterations in sleep architecture were observed in subjects, as evidenced by electroencephalogram (EEG) recordings conducted one week after cessation of daily repeated formaldehyde exposure (Sorg et al. 2001b). This repeated, low-level exposure not only induced behavioral changes such as heightened anxiety and altered sleep patterns upon subsequent formaldehyde exposure but also exacerbated fatigue. To emulate an occupational formaldehyde exposure scenario, Mei et al. (2016) conducted a study where 16 adult male mice were exposed to gaseous formaldehyde at a concentration of 3 mg/m³ for seven consecutive days. Their findings revealed that formaldehyde exposure induces intense oxidative stress by reducing systemic glutathione levels, particularly, brain melatonin concentrations, which was accompanied by hippocampal neuronal death and subsequent impairment in spatial memory. Zhou et al. have highlighted the disturbance of circadian rhythm and melatonin levels as an early indicator in the progression of Alzheimer’s disease (AD), which correlates with the advancement of AD neuropathology. Acknowledging the pivotal role of circadian regulation in AD, researchers have employed melatonin as a therapeutic agent in combination with light regulation to treat AD patients. Their results indicated that these interventions may help postpone the decline in cognitive abilities among AD individuals (Zhou and Liu 2012).

We hypothesize that formaldehyde metabolism is intricately linked to the regulation of the circadian rhythm, although further experimental validation is required. First, melatonin plays a crucial role in regulating circadian rhythms and sleep patterns (Ahmad et al. 2023). Formaldehyde, acting as a precursor, participates in the synthetic pathway of melatonin from serotonin (Binkley et al. 1988; Bolliet et al. 1996; Coon et al. 2001; Germann et al. 2016; Pham et al. 2023), suggesting a potential impact of formaldehyde on circadian rhythms. Second, the S-adenosyl-L-methionine (SAM) /S-adenosyl-L-homocysteine (SAH) ratio shows circadian rhythms, in which formaldehyde acts as a donor of methyl group, participating in methylation and demethylation of histone, DNA and RNA (González-Suárez and Aguilar-Arnal 2024). Third, formaldehyde is recycled through the folate cycle (Bailey 1995) and methionine cycle (Finkelstein and Mudd 1967) pathways (Tyihák et al. 1998; Chon et al. 2017; Burgos-Barragan et al. 2017; Morellato et al. 2021), positioning it as a potential regulator of melatonin synthesis. At last, serotonin metabolism, which influences the circadian rhythm, may also be modulated by the formaldehyde cycle (Pietraszek et al. 1990; Ciarleglio et al. 2011), further implicating formaldehyde as an influential factor in circadian rhythm regulation (Fig. 11.1). However, whether melatonin can ameliorate circadian rhythm disorders by regulating endogenous formaldehyde metabolism remains to be investigated.

Fig. 11.1

Schematic diagram of formaldehyde’s participation in melatonin synthesis through the formaldehyde cycle. Formaldehyde acts as a donor of methyl group to NAS in the synthesis of melatonin. The SAM/SAH ratio is involved in circadian rhythms. NAS N-acetylserotonin, SAH S-adenosyl-L-homocysteine, SAM S-adenosyl-L-methionine

Conditions like arthritis, asthma, and hypertension exhibit circadian variations, necessitating timed drug release for optimal efficacy. Aligning drug delivery with circadian rhythms can significantly enhance therapeutic outcomes for patients. Intriguingly, Kriplani et al. (2021) innovated a pre-programmed pulsatile drug delivery system tailored for chronotherapeutics, utilizing an optimal exposure to a formaldehyde/isopropanol (2/1) vapor mixture. They achieved successful floating and pulsed release of an antihypertensive drug within a “3Cap” system, activated by formaldehyde exposure. This breakthrough offers a revitalizing approach to existing drug molecules by integrating circadian rhythms into their delivery (Kriplani et al. 2021).

Beyond exogenous formaldehyde exposure, Li et al. (2016c) observed that endogenous formaldehyde concentrations in urine follow a rhythmic pattern, peaking around 8:00 am, dipping to their lowest levels at noon, and then rising again towards midnight. To validate the stability of this rhythm, a group of participants underwent water deprivation from morning to noon, with subsequent urine formaldehyde levels assayed. Compared to control subjects, while the formaldehyde levels at noon were notably higher in the water-deprived group, the overall rhythmic pattern remained largely intact (Li et al. 2016c). Furthermore, intraperitoneal injection of melatonin was found to markedly ameliorate formaldehyde-induced sleep disorders, reverse memory decline, and restore brain melatonin levels (Mei et al. 2016). These findings hint at a potential link between formaldehyde and sleep rhythms, possibly mediated through its effects on melatonin and catecholamine (norepinephrine and epinephrine) metabolism.

2.2 Formaldehyde Exposure Affecting Water Intake Rhythm

To delve into the interplay between formaldehyde and circadian rhythm, Li et al. initially compared the water-intake patterns of 1-month-old and 10-month-old mice, uncovering a decline in both the frequency and volume of water consumption among the older mice (Li et al. 2012). As part of their investigation, they administered intraperitoneal injections of formaldehyde (0.5 mg/kg, once daily) to a cohort of mice for a week, subsequently monitoring their water-intake patterns. Notably, both the frequency and volume of water intake significantly decreased in the formaldehyde-treated group compared to a saline-injected control group (Li et al. 2016c). Intriguingly, the formaldehyde-exposed mice also exhibited alterations in their hourly water-intake frequency, indicating that formaldehyde alters the daily rhythm of their water-drinking habits. Additionally, Mei et al. demonstrated that formaldehyde impacts the melatonin metabolism. Intraperitoneal injection of melatonin significantly mitigated formaldehyde-induced hippocampal neuronal death, while restoring brain melatonin levels and reversing memory decline. Their findings further revealed that formaldehyde directly inactivates melatonin both in vitro and in vivo (Mei et al. 2016). Prior studies have highlighted the potential of melatonin supplementation to ameliorate biological rhythmic disorders and age-related cognitive decline (Maurizi 1987; Skene et al. 1990). Taken together, these data lend credence to the hypothesis that formaldehyde exposure disrupts the daily biological rhythms of animal behavior (Li et al. 2016c).

Exposure to environmental risk factors can induce oxidative stress and disrupt the regulation of the circadian clock, thereby interfering with the crucial 24-hour cycles that govern biological functions (Daiber et al. 2022). A quintessential example of this is the experience of astronauts in space, who encounter disturbances in their circadian rhythm (Gundel et al. 1993; Stampi 1994). During prolonged missions in space, astronauts are inevitably exposed to not only microgravity and space radiation but also the hypomagnetic field (HMF) (Mo et al. 2014). Various experimental studies in animals have demonstrated the adverse effects of HMF on the circadian rhythms, which may lead to a range of health issues including sleep disorders, metabolic dysfunction, and neurological diseases.

In animal studies, long-term exposure to HMF has been observed to interfere with the circadian activities of various species (Bliss and Heppner 1976; Jiang et al. 1998; Zamoshchina et al. 2012). Specifically, rats exhibited desynchronized cerebral biorhythms following a three-month breeding period in HMF conditions (Zaporozhan et al. 2002). Furthermore, it is well-documented that memory is intricately linked to biological rhythms (Xu et al. 2021). Chicks hatched in an HMF of approximately 2 nanoteslas (nT) experienced impairments in gustation-related memory (Wang et al. 2003). Similarly, Drosophila offspring, after being bred for ten generations in an HMF, displayed deficiencies in vision-related learning and memory (Zhang et al. 2004). Collectively, these experimental findings suggest that HMF not only alters the circadian rhythms of animals but also adversely affects their cognitive abilities.

At the molecular level, we hypothesize that exposure to HMF is implicated in endogenous formaldehyde dysmetabolism. This hypothesis is supported by the following observations (1) Formaldehyde serves both a donor for the methylation of DNA, RNA, and histones, and a product of demethylation processes, as we are well aware. (2) DNA methylation was affected during the differentiation of embryonic stem cells exposed to HMF (Baek et al. 2019). (3) Histone methylation plays a crucial role in the circadian clock machinery, which operates at the intersection of circadian rhythms in transcription and metabolism (González-Suárez and Aguilar-Arnal 2024). (4) Formaldehyde is also involved in the methylation of norepinephrine, leading to the formation of epinephrine, and neurotransmitters that participate in the regulation of circadian rhythms (Rao et al. 1995). (5) Mei et al. (2016) observed that formaldehyde directly inactivates melatonin both in vitro and in vivo.

Additionally, we cannot overlook the effects of microgravity and radiation on formaldehyde metabolism in space. Recently, Mei et al. (2024) discovered that formaldehyde is associated with memory and motor impairments under a simulated weightlessness condition. Astronauts commonly face oxidative stress and neurodegeneration in space. Formaldehyde has been implicated in oxidative stress, neurodegeneration, and circadian rhythm disruptions under simulated-space environment conditions, such as HMF, microgravity, or radiation on the earth (Xu et al. 2021), as well as in actual space environments in the future.

3 Alterations in Neuropsychological and Emotional Behaviors

Emotion is a multifaceted experience encompassing consciousness, bodily sensations, and behavior that reflects an individual’s mental state. Emotional outcomes can be broadly classified as positive or negative, with negative emotions encompassing a spectrum of unpleasant feelings such as anxiety, anger, depression, and sadness. Emotions exert a profound influence on human health, operating through neural, humoral, endocrine, and immune mediation mechanisms to affect the physiological functions of the body’s tissues and organs. Numerous studies have reported a close association between formaldehyde exposure and negative emotional states. The underlying mechanism may involve formaldehyde and its derivatives targeting the cortex and hippocampus, as well as specific neurotransmitter receptors involved in emotional regulation, including 5-hydroxytryptamine (5-HT) receptors, dopamine (DA) receptors (Li et al. 2016a), and opioid receptors (Zhuang et al. 1999). In this section, we delve into the research evidence concerning the effects of formaldehyde exposure on emotional behaviors.

3.1 Formaldehyde and Depression

Formaldehyde exposure induces emotional and behavioral manifestations such as depressive-like behaviors in both animals and humans. Research has established a correlation between environmental formaldehyde exposure and depressive symptoms (Guo et al. 2024). A notable study revealed that among workers handling composite materials containing phenol–formaldehyde, approximately 19% had a prior history of depression (Parks and Pilisuk 1991). Furthermore, McEnery et al. (2023) reported a case involving a 16-year-old male who intentionally ingested windshield wiper fluid laden with methanol, subsequently developing a depressive medical history. Fortunately, he recovered through hemodialysis and administration of fomepizole, which inhibits the enzymatic conversion of methanol into formaldehyde. More recently, Xu et al. (2023) demonstrated that the impact of formaldehyde exposure varies among human subjects with differing levels of physical activity, highlighting an increased risk of depression associated with such exposure. In another study, intolerance to chemicals, particularly formaldehyde, was observed in 63.1% of pathologists. Notably, 42% of these subjects reported experiencing depression and burnout (Khan 2024).

In contrast to human studies, Aydin et al. (2023) conducted an experiment where they intraperitoneally injected formaldehyde into rats and observed apoptosis in the hippocampal CA1 and CA3 regions especially in male rats following acute exposure. Notably, under their experimental conditions, they did not detect any impairments in learning and memory nor did they observe any effects on depression or anxiety during both acute and chronic periods. However, Zhao et al. (2024) employed a different approach by administering a one-week intraperitoneal injection of lipopolysaccharide (LPS) to activate semicarbazide-sensitive amine oxidase (SSAO) in the midbrain vascular endothelium, thereby producing formaldehyde. They proposed that formaldehyde derived from LPS in the midbrain serves as a direct precipitating factor for depression. Findings from previous studies have also corroborated the intimate link between formaldehyde and depression. Wang et al. (2022) further contributed to this field by designing a two-photon fluorescent agent (TFCH) to visualize malondialdehyde (MDA) and formaldehyde simultaneously. Using this agent, they observed a synchronous increase in both MDA and formaldehyde in the brains of living mice exhibiting depressive symptoms. This finding suggests that depression is associated with elevated levels of formaldehyde and possibly other aldehydes, as supported by Yuan et al. (2023). A plausible theory explaining formaldehyde-induced depression might proceed as follows: Exposure to formaldehyde, functioning as a stressor, could activate the hypothalamic–pituitary–adrenal (HPA) axis, leading to an elevation in glucocorticoid levels (Dallman et al. 2003; Makino et al. 2002; Sorg et al. 2001a). These glucocorticoids, in turn, regulate the HPA axis response through negative feedback mechanisms involving glucocorticoid receptors (GRs) (Raone et al. 2007). Notably, the hippocampus, a component of the limbic system crucial for emotion, learning, and memory, exhibits the highest levels of adrenocorticosteroid receptor and mRNA expression (Reul and de Kloet 1985; Aronsson et al. 1988; Reul et al. 1989). Consequently, the hippocampus is particularly vulnerable to the adverse effects of glucocorticoids on emotional processing, learning and memory, including long-term potentiation (Diamond and Rose 1994; Bodnoff et al. 1995). Repeated stress exposure and prolonged glucocorticoid treatment have been shown to decrease the levels of brain GRs, especially in the hippocampus (Huot et al. 2004; Kitraki et al. 2004). Li et al. conducted open-field tests (OFT), elevated plus-maze tests (EPM), and forced swimming tests (FST) to assess anxiety and depression-like behaviors following repeated formaldehyde exposure. They found that repeated formaldehyde exposure reduced hippocampal GR levels (Li et al. 2016a). This reduction in hippocampal GRs impairs the negative feedback regulation of corticosterone (CORT) levels (Kitraki et al. 2004), resulting in heightened CORT levels and increased susceptibility to depression and anxiety.

Alterations of emotional behaviors following formaldehyde exposure may be linked to changes in dopamine (DA) levels, given that DA is a pivotal neurotransmitter regulating emotional fluctuations and motor activity (Gainetdinov et al. 1999; Rodgers et al. 1994; Zhuang et al. 1999; Zhou and Palmiter 1995). Acute exposure to formaldehyde at a concentration of 5 ppm has been shown to decrease motor activity in rats while concurrently increasing DA levels and its enzymatic metabolites in the hypothalamus (Boja et al. 1985). Another study revealed that inhaling formaldehyde at a concentration of 13.5 ± 1.5 ppm for two weeks enhances aggressive behavior and boosts DA levels in the frontal cortex synaptosome of rats (Liu et al. 2009). Tyrosine hydroxylase (TH), a key enzyme that controls the rate of DA synthesis and serves as an indicator of DA production, is widely distributed throughout various regions of the rat brain. Li et al. reported that exposure to different concentrations of gaseous formaldehyde results in varying degrees of anxiety, depression-like behaviors, and cognitive decline. These effects may be associated with alterations in hippocampal GRs and brain TH levels (Li et al. 2016a).

3.2 Formaldehyde and Anxiety

While anxiety, another type of nervous disorder, differs from depression, many individuals who develop depression have a prior history of anxiety disorders (https://​adaa.​org/​understanding-anxiety). It is common for those with anxiety disorders to also experience depression (Horwitz 2010). These two psychosomatic disorders frequently coexist. Similarly, anxiety-like behavior has been noted in mice exposed to formaldehyde for a week (Li et al. 2016a). The relationship between formaldehyde exposure and anxiety has been investigated using the elevated plus-maze test and open-field test. Malek et al. (2004) observed that even a brief two-hour exposure of mice to various concentrations of formaldehyde vapor (1.1, 2.3, and 2.5 ppm) significantly impacted their locomotor and exploratory activities in the open field. Notably, these alterations in behavior persisted for 24 h after exposure, suggesting that formaldehyde has the potential to induce emotional and mood changes, or even disorders.

Formaldehyde has been employed as an inducer in animal models to experimentally investigate pain-associated anxiety (Rahman et al. 1994a, b). In a study focusing on chemical intolerance, Sorg et al. observed that repeated exposure to low levels of formaldehyde not only produced and exacerbated anxiety but also induced sleep disturbances and/or fatigue (Sorg et al. 2001b). Li et al. administered formaldehyde intraperitoneally to mice once daily for seven days, resulting in a decrease in brain 5-hydroxytryptamine (5-HT) levels compared to the control group. Concurrently, the formaldehyde-treated mice exhibited heightened sensitivity, irritability, and slower learning in the “Shuttle box” behavioral assay compared to those receiving water as a control (Li et al. 2016a, b, c). Behavioral sensitization occurred after seven days of formaldehyde injections, aligning with previous findings reported by Sorg et al. (2001b) regarding formaldehyde-induced anxiety. Similarly, behavioral sensitization, irritability, and anxiety were also observed in monkey trials after the animals had consumed 3% methanol for three months. Demartini et al. (2022) exposed rats to formaldehyde in the orofacial region and evaluated trigeminal hyperalgesia. Their results indicated that trigeminal hyperalgesia was inversely correlated with motor or exploratory behavior but positively associated with anxiety-like behavior or self-grooming. In a related context, bone cancer pain is well-documented to cause depression, anxiety, fatigue, and sleep disturbances in patients, severely disrupting their daily quality of life and resulting in significant economic and psychological burdens. Chen et al. (2022) provided insights into a potential mechanism for formaldehyde-induced pain, demonstrating that endogenous formaldehyde upregulates the expression of transient receptor potential channels (TRPs), particularly TRP vanilloid 1 (TRPV1) in the dorsal root ganglion (DRG), thereby contributing to pain behavior.

Presented herein is previously unpublished data concerning a case study involving 37 employees (17 males and 20 females, aged 28–55 years, with an average age of 38 years) from a company who complained of air pollution caused by formaldehyde or other organic compounds in their workplace. These individuals expressed concerns about their health due to the presence of a formaldehyde odor. Some exhibited anxiety-related symptoms such as headaches, vertigo, nausea, indigestion, dry mouth, fatigue, and itchy skin (World Health Organization 2009; Testa et al. 2013). The authors collected urine samples from 28 of these employees and measured the concentrations of urine formaldehyde using high-performance liquid chromatography (HPLC) coupled with dinitrophenylhydrazone (DNPH). Notably, 60.7% (17/28) of the participants had urine formaldehyde levels that were significantly higher compared to an age-matched normal control group (5.9 ± 0.62 μM). The most irrational and excessively worried individual, who had the highest concentration of endogenous formaldehyde (18.28 μM), worked in the same office as two others with formaldehyde levels of 15.13 and 12.26 μM. These employees complained of an airborne formaldehyde odor in their office and felt agitated and restless. It is plausible that the wood desks they used may have contained excessive formaldehyde that was released into the office air. However, it is challenging to conclusively determine that their anxious symptoms were directly caused by formaldehyde toxicity, as their behaviors were also influenced by emotional factors. Additionally, the sample size of 28 urine samples was too small to draw definitive conclusions. Referring to the reports by Kilburn et al. (1985a, b, 1998), these data suggest that long-term exposure to formaldehyde may affect human mood, leading to anxiety and sensitization. As early as the 1980s, formaldehyde was found to react with serotonin to form a fluorescence product (Wreford and Smith 1980). The formaldehyde condensation reaction was also used to quantify 5-hydroxytryptamine in mast cells (Enerbäck et al. 1997). It appears that high concentrations of formaldehyde may deplete serotonin, which can impact an animal’s mood. Therefore, it is recommended that the determination of endogenous formaldehyde should be considered for individuals who have been exposed to formaldehyde for an extended period.

4 Alterations in Neurobiological Behaviors

4.1 Olfactory Dysfunction

Formaldehyde, a colorless gas characterized by a distinct pungent odor, interacts readily with the ε-amino groups of lysinyl residues within olfactory receptors. This interaction leads to the formation of Shiff’s base, effectively blocking the receptors. Remarkably, even at very low concentrations, formaldehyde can be perceived through olfaction, causing nasal lesions. Prior research by Apfelbach and Weiler (1991) has demonstrated that low-level exposure to formaldehyde (0.25 ppm over 130 days) impairs odor sensitivity. Furthermore, Zhang et al. (2014) reported that brief exposure to higher concentrations (13.5 ± 1.5 ppm, administered twice daily for 30 min over 14 days) compromised the olfactory function of rats in a buried food pellet test. Lang et al. (2008) suggested that olfactory disturbances may arise at concentrations as low as 0.3 ppm. Prolonged formaldehyde inhalation alters cellular morphologies within the olfactory bulb. Additionally, as a potent irritant, formaldehyde significantly influences sleep quality, which is a crucial factor in predicting indoor air quality (IAQ) perceptions (Fritz et al. 2022). Repeated low-level exposure to formaldehyde induces behavioral shifts, including heightened sensitivity to the chemical, manifested through altered sleep patterns and/or fatigue, as well as increased anxiety upon exposure (Sorg et al. 2001b). Given the profound impact of formaldehyde on the olfactory system, it is imperative to monitor formaldehyde levels in both indoor environments and occupational settings where exposure is frequent.

MicroRNAs (miRNAs), a class of small noncoding RNA molecules, plays a pivotal role in a diverse array of biological phenomena, encompassing cell cycle regulation, apoptosis, and numerous developmental and physiological processes. These include the differentiation of olfactory precursors, the morphogenesis of olfactory neurons, and neurogenesis. In a study conducted by Li et al. (2015), the molecular mechanisms underpinning formaldehyde-induced olfactory dysfunction were examined. Their findings revealed that formaldehyde inhalation significantly altered the miRNA expression profile within the olfactory bulb. Utilizing high-throughput microarray technology, they identified 18 miRNAs that were upregulated and 7 miRNAs that were downregulated. Notably, miR-199a, miR-146b, and miR-200a exhibited the most pronounced changes (Li et al. 2015). Furthermore, prolonged formaldehyde exposure was found to augment the count of tyrosine hydroxylase-immunopositive periglomerular cells in the primary olfactory bulb of mice, as reported by Hayashi et al. (2004). Tyrosine hydroxylase catalyzes the conversion of tyrosine to dopamine (DA), utilizing tetrahydrobiopterin and molecular oxygen as cofactors. The olfactory bulb of mammals harbors a substantial population of dopaminergic neurons within the glomerular layer, and dopamine has been established as a modulator of olfactory information processing. Synaptosomal-associated protein 25 (SNAP25), a presynaptic plasma membrane protein crucial for the regulation of neurotransmitter release, is abundantly expressed in the olfactory bulbs. Zhang et al. (2014) observed a decrease in SNAP25 protein expression following formaldehyde exposure. These findings collectively suggest that formaldehyde may impair olfactory function by disrupting the neurotransmitter system.

4.2 Algesthesia

Formalin, an aqueous solution comprising formaldehyde, selectively targets and degrades primary sensory neurons responsible for mediating chemogenic pain, making it a frequently utilized tool in algesthesia research. The rodent formalin model serves as a valuable platform for assessing the impact of pain and analgesic compounds on laboratory animals (Tjolsen et al. 1992). Administration of formalin into a rodent’s paw elicits a biphasic nociceptive behavioral response, characterized by both early and late phases. The early-phase response is likely triggered by direct activation of small primary afferent signals, whereas the late phase is dependent on a combination of peripheral tissue inflammation and functional alterations in the dorsal horn of the spinal cord. This model stands as a reliable and accessible test for studying nociception, prompting extensive research into uncovering its mechanisms. One study, conducted by McNamara et al. (2007), pinpointed transient receptor potential cation channel, subfamily A, member 1 (TRPA1) as the primary site of formalin’s pain-inducing action. The activation of this excitatory channel underpins the physiological and behavioral responses associated with this model of pain hypersensitivity.

Long-term pain can lead to anxiety, depression, and various emotional disturbances, ultimately compromising overall health. Exposure to high concentrations of formaldehyde, whether chronic or acute, triggers inflammatory pain and edema (Dubuisson and Dennis 1977; Dutra et al. 2013; Godin et al. 2015). Mogil, in his review of animal pain models, emphasizes the complexity of pain and cautions researchers to scrutinize these models carefully, acknowledging their inherent limitations (Mogil 2009). Intriguingly, cancer tissues have been found to directly secrete endogenous formaldehyde. Low concentrations of formaldehyde exacerbate metastatic bone cancer pain through TRPV1 activation, particularly in acidic tumor microenvironments (Zakharov et al. 2020). Recent studies have highlighted the role of the endocannabinoid system (Wang et al. 2015) and the nuclear factor kappa B (NF-κB) pathway (Santamaria-Anzures et al. 2023) in modulating formalin-induced nociceptive behavior and inflammation in both the peripheral and central nervous systems.

4.3 Effect on Motor Activities

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder characterized by the deterioration of both upper and lower motor neurons, leading to muscle weakness and significant impairments in physical function. As the disease advances, it can affect the nerves controlling breathing and other vital bodily functions, ultimately resulting in fatality. Despite extensive research, the precise etiology of ALS remains elusive.

Animal models and in vitro experiments have demonstrated neurotoxic effects of formaldehyde, suggesting a potential link to ALS. Several epidemiological studies have been conducted to investigate the relationship between ALS and formaldehyde exposure. Weisskopf et al. (2009) conducted a prospective cohort study involving over one million participants from the American Cancer Society’s Cancer Prevention Study II, observing a significant dose-response relationship between increasing years of formaldehyde exposure and the risk of ALS. Additionally, Fang et al. (2009) reported that certain occupations and workplace exposures may be associated with an elevated risk of ALS. However, a cohort research of formaldehyde-exposed garment workers did not suggest that ALS is associated with formaldehyde exposure (Pinkerton et al. 2013). In 2015, Roberts et al. examined the association with ALS mortality and job-related formaldehyde exposure in the National Longitudinal Mortality Study (NLMS). Their results indicated that the workers with a high probability of formaldehyde exposure, such as funeral directors, had an almost threefold greater rate of ALS-related deaths compared to those with lower exposure levels (Roberts et al. 2016).

According to Spencer (2018), formaldehyde-induced DNA damage has been implicated in the development of ALS and related neurodegenerative disorders. Bioinformatics analysis further supports this connection, revealing a significant association between formaldehyde exposure and ALS (Rana et al. 2021). Among the most relevant genes identified are tumor necrosis factor (TNF), a key pro-inflammatory marker, and superoxide dismutase (SOD1 and SOD2), indicators of oxidative stress. Moreover, Rana et al. (2021) found that formaldehyde significantly impacts vitamin B12 and folate metabolism, as well as pathways associated with ALS. Lee et al. (2024) described another intriguing aspect, suggesting that endogenous neurotoxins, including formaldehyde produced by the gut microbiota, can be transported to the central nervous system (CNS), causing damage to neurons responsible for motor function. Gut dysbiosis, characterized by an imbalance in the gut microbiome, contributes to increased concentrations of formaldehyde and other cytotoxins, which may potentially play a role in the pathogenesis of ALS. However, more research is needed to fully elucidate these relationships (Lee et al. 2024).

4.4 Primary Open-Angle Glaucoma

Primary open-angle glaucoma (POAG) is a prominent global cause of irreversible blindness. Increasing evidence points to a connection between POAG and AD (Bayer et al. 2002). Tsilis et al. (2014) observed a heightened incidence of POAG in AD patients. To uncover the risk factors associated with POAG, Cui et al. conducted a study to investigate the correlation between endogenous formaldehyde levels and POAG. By detecting the endogenous aldehyde with high-performance liquid chromatography (HPLC) in a double-blind manner (Cui et al. 2016), they found that endogenous formaldehyde level is positively correlated with the neuronal defects in POAG. These findings further implicate endogenous formaldehyde in the pathobiology of neurodegenerative diseases.

5 Other Psychosomatic Behaviors

In addition to its effects on central nervous system (CNS) functions, formaldehyde can also induce a range of neurological symptoms, including seizures, autism, and amnesia. Kilburn (1994) assessed the impact of formaldehyde on CNS function in three patients, all of whom were disabled, with two experiencing seizures. Perna et al. traced a case of epilepsy linked to formaldehyde exposure, suggesting that chronic exposure heightens sensitivity to formaldehyde, resulting in three tonic–clonic seizures, severe amnesia, and other cognitive impairments (Perna et al. 2001). Furthermore, in utero exposure to environmental toxins, including formaldehyde, is considered a risk factor for childhood autism, attention-deficit hyperactivity disorder, and neurodevelopmental disorders (von Ehrenstein et al. 2014; Nakaoka et al. 2021). Residents of trailers constructed with particleboard contaminated with formaldehyde reported symptoms such as headaches, nosebleeds, and stomachaches (Madrid et al. 2008). Formaldehyde also affects other sensory organs; for example, indoor exposure to formaldehyde irritates the nasal mucosa. In a study by Hisamitsu et al. (2011), students with preexisting allergic rhinitis exhibited temporary abnormalities in olfactory tests and increased nasal mucosal hypersensitivity to histamine after exposure to high concentrations of formaldehyde in their environment, although these effects were transient.

6 Potential Mechanisms Underlying Formaldehyde-Induced Neuropsychiatric Diseases

Exposure to exogenous formaldehyde directly impairs the mucous membranes of the respiratory tract and eyes. Prolonged or acute exposure to high concentrations of formaldehyde disrupts receptor function in the mucous epithelium and can even lead to necrosis of neurons and fibers, ultimately compromising olfactory and visual functions (Werner and Nies 2018). The degree of neural cell damage caused by formaldehyde varies with the concentration and duration of exposure. While brain cells possess the capacity to produce and eliminate formaldehyde, severe exposure disrupts their metabolic processes, contributing to psychosomatic behavioral disorders and neurodegenerative diseases. In the subsequent paragraphs, we delve into the clinical and experimental data to elucidate the mechanisms by which formaldehyde exposure triggers neuropsychiatric diseases.

Chemical modifications of proteins have been well documented to play a pivotal role in the pathophysiology of numerous human diseases, including age-related diseases and neurodegenerative disorders. Both endogenous and exogenous formaldehyde react with side-chains in proteins such as amino group and thiol group, which may serve as a biomarker of formaldehyde exposure (Liu et al. 2016). Many mechanistic studies on formaldehyde toxicity have utilized cytotoxic concentrations sufficient to induce cell death. However, to simulate real-life exposure levels, normal human keratinocytes were exposed to 200 μM formaldehyde, resulting in pro-inflammatory responses (Lee et al. 2016). Therefore, formaldehyde-induced inflammation may be another contributing factor to neuronal impairment and brain dysfunction (see Chap. 12). Hu et al. (2021) observed that formaldehyde exposure upregulated ferritinophagy in mouse hippocampal neuronal HT22 cells and the hippocampus of Sprague-Dawley rats. Silencing the expression of the nuclear receptor coactivator 4 (NCOA4) mitigated formaldehyde-induced toxicity in HT22 cells (Hu et al. 2021). These findings provide a potential mechanistic insight into formaldehyde-induced neurotoxicity.

The potential chronic and debilitating effects of formaldehyde have been linked to the formation of biologically active epoxides in proximity to axons. These epoxides bind to neurofilament proteins, causing them to swell and proliferate, which is hypothesized to lead to demyelination (Kilburn et al. 1987; Savolarnin 1977). Exposure of cultured astrocytes and neurons to formaldehyde has been shown to accelerate glycolytic flux through the rapid multidrug resistance protein 1-mediated export of glutathione (Tulpule and Dringen 2013). Alterations in brain cell metabolism may contribute to the impaired cognitive performance observed following formaldehyde exposure. Neurotransmitters such as acetylcholine (ACh), dopamine (DA), serotonin (5-TH), and N-methyl-D-aspartate (NMDA) play crucial roles in psychosis and neurosis. Rats exposed to low levels of formaldehyde exhibited decreased motor activity accompanied by neurochemical changes in DA and serotonin neurons (Boja et al. 1985). Workers exposed to formaldehyde concentrations ranging from 0.024 to 0.74 ppm with the increased alcohol dehydrogenase III ADH32–2 genotype had higher acetylcholinesterase (AChE) levels compared to controls, suggesting that the neurotoxic effects of formaldehyde are dependent on AChE activity (Zendehdel et al. 2016). Furthermore, formaldehyde administration decreases norepinephrine (NE) levels in the brains of rodents. Tong et al. provided evidence that accumulated formaldehyde is a significant endogenous factor contributing to aging-associated NE depletion and cognitive decline (Mei et al. 2015). High concentrations of formaldehyde gradually inactivate NMDA receptors by cross-linking the NR1 and NR2B subunits via the C232 residue (Ai et al. 2019). This inactivation can impair synaptic plasticity and memory formation, as NMDA receptors are essential for these processes. These neurotransmitters—ACh, DA, 5-TH, NE, and NMDA receptors—are involved not only in cognitive function but also in mood and emotion. The widespread effects of formaldehyde on these systems indicate that it may contribute to both cognitive impairment and mood disorders through multiple pathways.

Reactive aldehydes, particularly formaldehyde, have been implicated in the etiology of several neurological and psychiatric disorders, with the relationship between them being mediated through multiple pathways. Elevated levels of formaldehyde and upregulation of semicarbazide-sensitive amine oxidase (SSAO) have been observed in conditions such as cerebrovascular disorders, alcohol abuse, diabetes, and AD, suggesting that formaldehyde may play a role through enzymatic regulation. Another plausible mechanism involves the glutamate pathway, as formaldehyde has been shown to affect the regulation of second messengers, including AKT and p38, potentially altering neuronal signaling (Song et al. 2010). Formaldehyde has also been associated with anxiety disorders, depression-like behavior, and impairments in cognitive ability, which may be mediated through its impact on hippocampal glucocorticoid receptors (GRs) and brain tyrosine hydroxylase (TH) levels (Li et al. 2016b). Formaldehyde has the potential to alter the concentration or activity of neurotransmitters that are crucial for cognitive development. These findings highlight the complex and multifaceted ways in which formaldehyde may contribute to neurological and psychiatric disorders.

7 Debate and Comprehensive Evaluation

Despite a wealth of literature documenting the potential link between formaldehyde exposure and cognitive impairment, rigorous scrutiny of compelling evidence is imperative, particularly in scenarios involving environmental exposure where other toxic gases may be present, and exposure time and dose are often uncertain. Evaluation methodologies, such as questionnaires and measurement scales, must meticulously account for individual factors including age, gender, education level, and psychological status. Criticisms have been raised regarding the conclusion that exogenous formaldehyde exposure impairs cognitive functioning, citing “selection bias in participant recruitment and unreliability in participant recall for acquiring data on critical background variables and exposure levels” (Williams and Lees-Haley 1998). In an animal study, despite observing apoptosis in hippocampal neurons, researchers did not detect impairments in learning, memory, depression, or anxiety following acute and chronic formaldehyde administration (Aydin et al. 2023). Therefore, when assessing neurobehavioral damage due to chemical exposure, it is crucial to consider the synergistic effects of neurophysiology and neuropsychological assessments, along with individual factors such as age and education level. Furthermore, animal models used in such studies should be more standardized to ensure reliability and validity of the findings.

Several inhalation studies utilizing labeled formaldehyde (13CD2) have consistently failed to detect DNA adducts outside the nasal tissue in rats and monkeys, leading to the conclusion that formaldehyde does not reach internal organs or the bloodstream (Lu et al. 2010, 2011; Swenberg et al. 2011). However, there are reports suggesting that exogenous formaldehyde exposure is associated with elevated formaldehyde levels in the brain (Tulpule and Dringen 2013; Tulpule et al. 2012; Li et al. 2020a, b). Our research has further shown that formaldehyde present in cerebrospinal fluid (Li et al. 2020a, b) can readily cross the blood–brain barrier (Malek et al. 2003a, b), potentially affecting neuroglia and nerve cells. Fine particulate matter smaller than 2.5 microns (PM2.5) can penetrate blood vessels and the blood–brain barrier (Ailshire and Clarke 2015; Ailshire and Crimmins 2014), and formaldehyde may adsorb onto these particles, thereby targeting tissue and cell receptors.

The hippocampus plays a pivotal role in the consolidation of short-term memory into long-term memory and spatial learning in humans and other animals (Lieberwirth et al. 2016). While brain formaldehyde accumulation is often attributed to endogenous sources, particularly metabolic disturbances, translating findings from animal and cellular experiments to humans requires caution (Worek et al. 2002). However, epidemiological studies and experimental research sufficiently underscore the importance of minimizing formaldehyde exposure. Various factors, including the mode, concentration, and duration of exposure, as well as species-specific metabolism pathways, significantly influence the outcomes of behavioral assessments. The transport and metabolism of formaldehyde in the body become increasingly well-understood. Despite the existence of multiple production and metabolism pathways for formaldehyde, the lysosome plays a crucial role in accommodating and transporting formaldehyde across cell membranes (Chen et al. 2017; Xiong and Zhu 2016) (see Chap. 2). Real-time formaldehyde detection in living organisms is essential for understanding its diverse functions in physiological and pathological processes. Advanced detection methods contribute to elucidating formaldehyde’s role in biological systems. For instance, reaction-based fluorescent/chemiluminescent probes enable real-time visualization of formaldehyde in vivo (Huang et al. 2022). However, further investigation into neurotoxic mechanisms is still necessary.

8 Precautionary Measures Against Formaldehyde Exposure

Formaldehyde is a prominent constituent of air pollution in both workplace and residential settings. Epidemiological studies and experimental evidence clearly indicate that formaldehyde poses significant health risks. To mitigate these risks, several precautions are recommended: (1) Enhance ventilation to dilute formaldehyde levels in indoor air. (2) Utilize air purifiers specifically designed to remove formaldehyde from the air. (3) Lime has been proven to be an effective agent in reducing formaldehyde concentrations in highly contaminated effluents (Moussavi et al. 2002). (4) Planting trees can help alleviate formaldehyde pollution in both air and water environments (Su and Liang 2015). (5) Incorporate antioxidant-rich foods, such as grapeseed (resveratrol), into your daily diet to lower formaldehyde levels in the body and safeguard health. (6) Eliminating sources of formaldehyde exposure is the most effective means of protecting health. (7) For information on pharmacological treatments for formaldehyde poisoning, refer to Chap. 18.

Numerous studies have highlighted the role of endogenous formaldehyde in neural dysfunction. Abnormalities in formaldehyde metabolism may result in excessive accumulation of formaldehyde in the brain during aging (Kou et al. 2022). Both endogenous formaldehyde scavenger like Coenzyme Q10 and exogenous scavengers such as NaHSO₃ have demonstrated the ability to reduce intracellular Aβ oligomers and extracellular senile plaques, thereby improving spatial memory in APP/PS1 mice (Fei et al. 2021). Additionally, consuming green tea and water regularly can help decrease levels of endogenous formaldehyde. Therefore, targeting the pathways involved in the production and degradation of formaldehyde may offer an effective strategy for treating neuropsychiatric disorders caused by formaldehyde metabolism imbalances in the brain.

9 Conclusion

Excess formaldehyde exhibits a multitude of detrimental effects on various human organs, including the brain, kidney, liver, lung, and blood vessels, with a particular impact on CNS. Epidemiological and experimental data consistently support formaldehyde’s role as a risk factor for neuropsychiatric disorders such as depression, anxiety, cognitive impairment, and circadian rhythm dysfunction. However, the precise mechanisms underlying how formaldehyde exposure leads to mental disorders remain elusive. Recent research has shown that formaldehyde induces β-amyloid deposition, Tau hyperphosphorylation, neurotransmitter dysregulation, and even neuronal death, all of which may contribute to brain impairment and neuropsychiatric disorders. To safeguard public health, it is imperative to strengthen studies on the impact of air pollution on neuropsychological disorders and to develop highly sensitive monitoring techniques for formaldehyde, along with effective protective measures. Further research is necessary to elucidate the relationship between long-term formaldehyde exposure and neuropsychiatric disorders. Meanwhile, insightful investigations are required to ascertain whether endogenous formaldehyde (or formic acid, an intermediate product) can serve as a biomarker for identifying anxiety or depression.

High-level exposure to formaldehyde has been shown to induce a variety of neuropsychiatric disorders, and elevated formaldehyde levels in the body fluids of AD patients have been frequently reported. Individuals can assess their risk of formaldehyde overexposure by detecting formaldehyde levels in their urine, serum, or cerebrospinal fluid. It is crucial to acknowledge that formaldehyde-induced neuropsychiatric disorders likely represent only a subset of mental health conditions and not all cases. The approach to addressing this issue should involve determining whether a patient with neuropsychiatric disorders exhibits associated formaldehyde metabolism disturbances. If formaldehyde metabolism disturbances are confirmed through the assessment of endogenous formaldehyde and formic acid, protective measures should be implemented to reduce exposure. This refined approach underscores the importance of targeted diagnosis and intervention, rather than presuming a direct link between all neuropsychiatric disorders and formaldehyde exposure.

Acknowledgments

This project was supported by National Key R&D Program of China (No.2022YFA1604504) and the Key Research Program of Chinese Academy of Sciences, (NO. ZDBS-ZRKJZ-TLC007).

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_12

12. Formaldehyde, Neuroinflammation, and Cognitive Impairment

Nianxin Kang¹, Ying Liu¹ and Rongqiao He2  

(1)

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China

(2)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Attention has been paid to the occurrence of neuroinflammation in the early stages of Alzheimer’s disease (AD), acting as a key factor in promoting the progression of AD. Neuroinflammation is generally characterized by the activation of microglia and astroglia, and the associated expression of proinflammatory cytokines and chemokines, which damage the nervous system. Numerous pieces of evidence prove that formaldehyde is closely related to learning, memory, and cognitive impairment in AD patients. Formaldehyde has been shown to elicit amyloid β (Aβ) deposition and Tau hyperphosphorylation, leading to cognitive impairment based on animal and clinical studies. Changes in concentrations of formaldehyde can be observed in general inflammation in different organs such as lung, liver, kidney, and circulating immune of brain. Furthermore, formaldehyde is usually used as an agent to induce pain, resulting in a marked inflammatory process in central and peripheral nervous system. As an inflammation-inducing factor, formaldehyde is able to activate microglia and astrocytes, leading to the release of proinflammatory cytokines and chemokines, by deteriorating the permeability of the blood–brain barrier (BBB), eliciting Aβ deposition and inducing Tau hyperphosphorylation in brain. In other words, formaldehyde participates not only in the general inflammation but may also in neuroinflammation, although the mechanisms by which formaldehyde-induced inflammation activates microglia and astroglia in central nervous system (CNS) still need further investigation.

Keywords

FormaldehydeNeuroinflammationMicrogliaAstrogliaBlood–brain barrier

Abbreviations

A

ACT

Antichymotrypsin

AD

Alzheimer’s disease

APOE

Apolipoprotein E

α2-M

α2-Macroglobulin

B

BACE1

β-Site APP-cleaving enzyme

BBB

Blood–brain barrier

C

CLU

Clusterin

CNS

Central nervous system

F

FA

Formaldehyde

FERMT2

Fermitin Family Member 2

G

GFAP

Glial fibrillary acidic protein

GWAS

Genome-wide association studies

I

Iba1

Ionized calcium-binding adapter molecule 1

IL-1β

Interleukin-1β

IL-6

Interleukin-6

L

LOAD

Late-onset AD

M

MR

Mendelian randomization

N

NFTs

Neurofibrillary tangles

NMDA

N-Methyl-D-aspartate

R

RAGE

Receptor for advanced glycation end-products

ROS

Reactive oxygen species

S

SP

Substance P

SSAO

Semicarbazide-sensitive amine oxidase

T

TJ

Tight Junctions

TNF-α

Tumor necrosis factor-α

TRPA1

Transient receptor potential ankyrin 1

TRPV1

Transient receptor potential vanilloid 1

1 Introduction

Alzheimer’s disease (AD) is the most common form of dementia. The accumulation of β-amyloid plaques and neurofibrillary tangles (NFTs) of hyperphosphorylated Tau protein are two hallmarks of AD. There are several hypotheses regarding AD pathogenesis, including the accumulation of amyloid-β, persistent inflammatory responses, regression of myelination, loss of DNA integrity, and so on (Wang et al. 2019). Growing evidence has suggested that AD pathogenesis is not only limited to the neuronal compartment but also strongly interacts with immunological processes in the brain. Additionally, misfolded and aggregated proteins can bind to pattern recognition receptors located on microglia and astroglia, which can, in turn, induce an innate immune response, characterized by the release of inflammatory mediators, ultimately playing a role in both the severity and the progression of the disease (Uddin et al. 2022).

O’Callaghan et al. (2008) discussed the definition of neuroinflammation, and noted the activation of microglia and astroglia and the attendant expression of proinflammatory cytokines and chemokines, which is often associated with damage in the CNS. Its academic status is generally accepted although controversy exists about the importance of neuroinflammation in AD (Hensley 2010). Many authors refer to microglial activation as an important event for neuroinflammation (the CNS prototypical inflammatory disease) (Bivona et al. 2023). Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer’s disease (Cui et al. 2023; Han et al. 2024) and depressive disorders (Shi et al. 2024). Filiou et al. emphasized that the designations of neuroinflammation and inflammation should not be interchangeable because neuroinflammation is involved very different sets of genes from those in inflammation. Neuroinflammation remains a term still in need of a precise definition (Filiou et al. 2014). Recently, Li et al. (2023) considered the effects of microglia and astroglia activation and the related cytokines in neuroinflammation and post-traumatic stress disorder. Recent studies have further highlighted the involvement of neuroinflammatory processes in AD-related brain lesions (Belkhelfa et al. 2024). For instance, postmortem analyses revealed significant tissue lesions across various brain regions, notably in the right middle frontal gyrus, cingulate gyrus, putamen, and hippocampus. These lesions, which included granulovacuolar degeneration, Hirano bodies, and neuritic plaques, were closely associated with the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and transforming growth factor-β (TGF-β), driven by the nuclear factor kappa B (NF-κB) activation pathway. These findings underscore the critical role of neuroinflammation in exacerbating neuronal damage and the potential of targeting these inflammatory pathways as a therapeutic approach in AD (Belkhelfa et al. 2024).

In fact, the role of formaldehyde (FA) in inflammation has been studied about 60 years. Formaldehyde-induced inflammatory reaction was observed by injecting it at the site in rats (Parratt and West 1957; Northover and Subramanian 1961). Formaldehyde, a common pollutant, posed severe risks to respiratory health by triggering pulmonary inflammation through immune activation and oxidative stress (Bhat et al. 2024). The brain produces FA through a variety of pathways, the most prominent of which are enzymatic reactions, such as semicarbazide-sensitive amine oxidase (SSAO, also called vascular adhesion protein 1, VAP-1), and cytochrome P450 (CYP450). Glutathione-dependent FA dehydrogenase (FDH or named ADH3) functions in maintaining homeostasis of FA levels in brain tissues. During the aging process, the ability of the FA metabolism enzyme system gradually becomes decreased. Accordingly, the imbalance may occur between endogenous FA generation and degradation, leading to the accumulation of FA (or formic acid) in brain tissue (Kou et al. 2022). SSAO is involved in the early stage of the inflammatory response (Becchi et al. 2017; Unzeta et al. 2021). Glia activation was observed in the mouse brain after FA treatment. Upon exposure to different concentrations of FA, resting microglia were activated with significant changes in Iba1 (ionized calcium-binding adapter molecule 1 as a marker for microglial cells). Astroglia activation was also observed with increased expression of glial fibrillary acidic protein (GFAP) in the cerebral cortex following formaldehyde exposure (Liu et al. 2018). Recently, more attention has been paid to formaldehyde-induced inflammation was paid in AD studies. Therefore, in this chapter, we discuss the relationship between FA and neuroinflammation, particularly the activation of microglia and astroglia, to broaden the potential mechanism of age-related cognitive impairment.

2 Formaldehyde and Neuroinflammation

Formaldehyde is a widespread environmental organic pollutant, and an endogenous metabolite in the human body at the same time. Elevation of FA in the body by endogenous and/or exogenous exposure may play important roles in cognitive impairment development. Recently, many studies have focused on evaluating the association between chronic exposure to FA and its neurotoxicity (Pant et al. 2021). DNA damage induced by FA promotes AD onset (Tian et al. 2024). In vivo and in vitro studies demonstrated that the mechanisms underlying FA toxicity are associated with inflammation, oxidative stress, and genotoxicity (Bernardini et al. 2022). Exposure to formaldehyde may exacerbate neuroinflammation through NF-κB activation in a mouse asthma model (Duan et al. 2018). Formaldehyde causes CNS damage and may accelerate the progression of AD (Wang et al. 2019). Endogenous and exogenous FA plays an important role in age-related cognitive impairment. Epidemiological studies have shown excess FA accumulates in AD patients, associated with impaired performance in learning and memory (Perna et al. 2001). As described by Wang et al. (2022b), correlation between urine FA and cognitive abilities showed the clinical spectrum of AD. Urine FA level as a diagnostic indicator has shown its potential possibility in age-related cognitive impairment (Chen et al. 2022).

In 1949, formaldehyde was injected into a rat’s foot as an “arthritic” reaction (noninfectious inflammation) (Selye 1949). After that, formaldehyde induced a local inflammation at the site of injection (Parratt and West 1957; Northover and Subramanian 1961). A local inflammation rapidly occurred when formaldehyde was injected. So far, formaldehyde as an inflammatory inducing or proinflammatory factor is widely used in inflammatory studies (Bernardini et al. 2022; Danielli et al. 2022; Farahani et al. 2021; Hasriadi et al. 2024).

In recent years, neuroinflammation and treatments for AD targeting neuroinflammation have developed considerably (Thakur et al. 2023; Si et al. 2023; Andronie-Cioara et al. 2023). Neuroinflammation, encompassing various inflammatory events in the CNS under pathological conditions, also participates in the AD process induced by FA. The levels of pro-inflammatory markers, including NF-κB, TNF-α, IL-1β, and COX-2, have been shown to be increased significantly in mice after 15.5 mg kg⁻¹ day⁻¹ FA exposure (Liu et al. 2018). Besides, significant increases in reactive oxygen species (ROS) and malondialdehyde levels and decreases in glutathione and superoxide dismutase levels have been reported after FA exposure in mouse brain (Liu et al. 2018). Huang et al. (2019) used FA to construct a neurotoxicity model and analyzed the inflammation of brain. The results revealed that the concentration of TNF-α and IL-1β in the FA group was the highest, with a significant difference from the control group, which might be caused by FA-induced oxidative stress in the brain of mice. However, the mechanism by which FA is associated with AD requires further investigation.

3 FA Is a Predisposing Factor of AD

Gaseous FA is a simple aldehyde and an organic molecule formed in the early evolution of earth. Participating in the formation of various organic compounds, formaldehyde may have played a role in prebiotic chemistry, but not the primary precursor of complex molecules such as proteins, amino acids, DNA, and RNA (Robertson and Miller 1995). However, high concentrations of FA exposure induce memory deficit in animals (Lu et al. 2008), and cognitive decline in humans (Kilburn et al. 1987). AD is a common neurodegenerative disease in the elderly characterized by persistent cognitive decline that has also been linked to disrupted FA metabolism. It was reported that urine-based FA was a potential biomarker for AD (Tong et al. 2017; Chen et al. 2022). In addition, urine FA level was significantly independently correlated with gender, plasma Aβ42, and P-Tau181/T-Tau, which further indirectly reflected the correlation between urine FA level and the disease severity of AD (Wang et al. 2022b). Using an activity-based fluorescence probe NP-FA, which possesses excellent blood–brain barrier (BBB) permeability, Wang et al. (2022a) found that FA levels in the AD brain are significantly higher than those in the normal brain. Similarly, increased FA levels have also been observed in the hippocampus of AD patients (Tong et al. 2011). As described by our further investigation, excess hippocampal FA can be an endogenous pathogenic factor in memory decline (Tong et al. 2013).

Excessive exposure to FA was reported to induce amyloid aggregation (Rizak et al. 2014; Zhao et al. 2021) and Tau protein aggregation and hyperphosphorylation in vitro and in vivo (Lu et al. 2013). The recovery of memory was associated with FA reduction in AβPPswe/PS1dE9 transgenic mice (Lu et al. 2021). Excess endogenous FA could induce AD-like pathologies and cognitive impairments in rodent studies and rhesus monkeys (Yang et al. 2014; Zhai et al. 2018). Elevated levels of FA in the body were associated with impaired performance in learning and memory in AD patients (Tong et al. 2017). Endogenous FA was also reported to regulate learning and memory via the N-methyl-D-aspartate (NMDA), the critical receptor for learning and memory by triggering associative synaptic plasticity (Ai et al. 2019). Elevated FA levels in the brain may play crucial roles in AD development, potentially through various mechanisms, including inflammatory progression. Thus, FA toxicity could be a significant contributing factor to AD pathology.

4 The Relationship Between Neuroinflammation: Two Opposite Points

Alzheimer’s disease is characterized by sustained neuroinflammation leading to memory loss and cognitive decline. Neuroinflammation may play a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful (Calsolaro and Edison 2016). The past decade has witnessed tremendous efforts in AD research. However, no effective treatment is available to prevent disease progression. In summary, there are two contrasting viewpoints on the effects of neuroinflammation in AD research.

On one hand, neuroinflammation in AD generally refers to an inflammatory response occurring within the CNS. However, there is no infiltration of adaptive or innate peripheral immune cells in the brain, and no detection of circulating cytokine levels during a microglial reaction, suggesting an independent inflammatory process within the brain, separate from recruited peripheral immune cells (Bivona et al. 2023). The postmortem studies on AD human brains have reported a lack of perivascular mononuclear infiltrates and generally no distinct histopathologic features compared to other neurodegenerative diseases (Filiou et al. 2014). In a recent clinical trial, an anti-inflammatory drug (tetracycline antibiotic minocycline) failed to delay progression in individuals with mild AD (Gyengesi and Münch 2020). These findings suggest that the effects of neuroinflammation on the onset and progression of AD need further investigation and clarification.

On the other hand, neuroinflammation is believed to play an important role in AD pathogenesis, alongside the classical pathological hallmarks such as misfolded and aggregated proteins (e.g., Aβ and Tau) (Si et al. 2023). These researchers defined “neuroinflammation” as involving the activation of innate immune cells (primarily microglia and astrocytes, but also including capillary endothelial cells and infiltrating blood cells), along with the upregulation of several pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, chemokines like CXCL1, CCL2, CCL5, ROS, and secondary messengers (NO and prostaglandins) (Michael et al. 2025). In the CNS, microglia and astrocytes are the primary mediators of inflammation and predominant candidates for investigations of neuroinflammatory processes in AD (Mi et al. 2023; Moonen et al. 2023; Daria et al. 2017; Hamelin et al. 2016).

Using inflammatory ligands and positron emission tomography, international colleagues have observed that neuroinflammation can be one of the earliest detectable pathological hallmarks in AD through the quantification of inflammation levels (Hall et al. 2017; Gispert et al. 2016). Sustained inflammatory response brings about detrimental effects, fueling neurodegeneration as the disease progresses. Peripheral immune dysfunctions occurred early in the disease, perhaps even prior to relevant pathogenic cerebral changes (Dá Mesquita et al. 2016). Chronic activation of the immune cells in the brain and immune cell trafficking from the periphery via the blood–brain barrier contribute to the neuroinflammatory response, which is participated in the neurodegenerative processes in AD (Leng and Edison 2021). In addition, promising effects of immune-based drugs in preventing Aβ accumulation in early AD have been reported (Pardo-Moreno et al. 2022; Thambisetty and Howard 2023). Next, we will discuss the role of microglia and astrocytes in AD and the involvement of FA in these processes.

4.1 Microglia Participate in AD

Microglia are CNS-resident immune cells and are the primary players in neuroinflammation. The role of microglia in the pathophysiology of AD is associated with their three phenotypes: steady-state, activated, and primed phenotype. Steady-state or naive microglia are always closely related to neuroprotection, producing basic cytokines, and carrying out housekeeping activities (Savage et al. 2019). Activated microglia perform aggressive and potentially harmful activity toward neurons because of the overexpression of chemokines and pro-inflammatory cytokines such as IL-1β, IL-8, and TNF-α in these cells. However, activated microglia also synthesize anti-inflammatory cytokines (Xu et al. 2022). The balance between pro- and anti-inflammatory molecules produced in microglia is the key element of brain homeostasis (Das and Chinnathambi 2019).

Microglia turn toward the aggressive, pro-inflammatory phenotype when activated microglial cells are repeatedly stimulated, further making the brain prone to excessive inflammation, which is related to the pathogenesis of neurodegenerative diseases instance for AD (Ising et al. 2019). Neuroinflammation tends to be considered as a vital driver of the disease in the context of neurodegenerative disease due to its inability to resolve on its own (Heneka et al. 2015). Numerous studies have strongly confirmed this point. A genome-wide association study (GWAS) with 1,126,563 individuals (90,338 cases and 1,036,225 controls) highlighted the enrichment of late-onset AD (LOAD)-associated genes in microglia (Wightman et al. 2021). Similar enrichment has previously been observed in nonhuman microglial cells (Jansen et al. 2019). Furthermore, the accumulation of activated microglia around damaged areas is one of the hallmarks of the neuroinflammation in AD brain (Cai et al. 2022). Recent studies have emphasized the crucial role of caspase-8 in microglia-driven neuroinflammation in AD. The deletion of caspase-8 in an Aβ mouse model significantly reduced Aβ deposition and microgliosis, demonstrating its role in regulating inflammasome activation and IL-1β release. These findings suggest that targeting caspase-8 may be a potential therapeutic strategy to mitigate neuroinflammation and disease progression in AD (Kumar et al. 2023).

4.1.1 Formaldehyde Activates Microglia Through Inducing Abeta Deposition

Monomeric Aβ has no neurotoxicity, while the Aβ dimer (two molecules of Aβ) and oligomer (Petrushanko et al. 2023) have been found to induce neuronal dysfunction in the early stage of AD (Zott et al. 2019). It is known that FA is one of the key players in inducing Aβ. Previous studies have indicated that FA could induce aggregation of Aβ in vitro (Rizak et al. 2014; Yang et al. 2014). It is worth noting that both FA and Aβ dimer levels are closely related to damage of learning and memory in AD patients (Zott et al. 2019; Tong et al. 2017; Lesne 2014). These results indicated their synergistic roles in promoting Aβ deposition and AD occurrence (Fei et al. 2021).

Microglia are potential diagnostic marker for the development and progression of AD (Wang et al. 2023). In diseased brains, microglial morphology and electrophysiological changes depend on the spatial location and stage of the disease. For instance, there are dramatic morphological and electrophysiological variations in amyloid plaque-associated microglia over time, but minor variations in plaque-distant microglia (Plescher et al. 2018). These temporal diversities could be attributed to the differential responses of microglia to different stimuli such as Aβ or Tau aggregation (Fig. 12.1). The aggregates of different species of Aβ could induce glial activation and the production of the anti-inflammatory cytokine, pro-inflammatory cytokines, chemokines, and ROS, all of which further lead to neuronal dysfunction and death (Akiyama et al. 2000). Aβ stimulates a cytoplasmic tricomplex called NLRP3 inflammasome and changes the microglial phagocytosis function to increase Aβ accumulation (Mata-Martínez et al. 2022). The in vivo imaging has revealed that microglia could help Aβ propagate in unaffected tissues as transporters (d’Errico et al. 2022). Apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC), an adapter protein released by active microglia, further accelerates plaque formation by causing oligomerize and aggregate of Aβ (Venegas et al. 2017). Microglia become more sensitive to inflammatory stimuli due to aging-related microglial senescence, which exacerbates Aβ pathology (Hu et al. 2021). For example, TNF-α and IFN-γ, which are pro-inflammatory cytokines produced by microglia, might impair their capacity to digest Aβ and block the production of Aβ-degrading proteases, potentially leading to plaque formation (Michelucci et al. 2009; Yamamoto et al. 2008).

Fig. 12.1

A putative schematic diagram for formaldehyde induces neuroinflammation

The receptors to recognize Aß species by microglia are mostly pattern recognition receptors, including CD14, CD47, α6β1 integrin, scavenger receptors (such as CD36), and toll-like receptors (such as TLR1, TLR2, TLR4, and TLR6). Conversely, these receptors activate molecular pathways that induce the changes of microglial phenotype (Alawieyah Syed Mortadza et al. 2018; Venegas et al. 2017). Activation of receptor of advanced glycation end-products (RAGE) also drives inflammatory responses in microglia and encourages oxidative stress in neurons (Deane et al. 2012). In addition, TREM2, a microglial surface receptor, plays a crucial role in the uptake of Aβ by microglia (Qin et al. 2021). Indeed, it has been demonstrated that older microglia have a lower response to Aβ in terms of phagocytosis and autophagy. Microglial Aβ-binding cognate receptors, including CD36, SR-A, and RAGE, are downregulated in old mice and AD brain, which point to an altered phagocytosis function with aging (Hickman et al. 2008). In short, Aβ may trigger numerous inflammatory signaling in microglia that may contribute to AD pathogenesis, but microglia could also help Aβ pathology expand because of their own senescence and functional degeneration.

4.1.2 SSAO and Microglia

Acute FA exposure induced early Alzheimer-like changes in mouse brain, including activation of microglia and astrocytes, increased BBB permeability, and changes in inflammation (Liu et al. 2018). As we know, FA is a major product of the deamination of primary amines catalyzed by SSAO, which activates transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors, which are predominantly expressed on nociceptors (Horváth et al. 2018). Activated of TRPA1 and TRPV1 may lead to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes (Corrigan et al. 2016). SSAO/VAP-1 respond to lipopolysaccharide (LPS) insult during the early stage of inflammation in the brain. LPS administration induces an increase in microglial response in various brain areas including the substantia nigra and striatum (Becchi et al. 2017). Those data suggest that formaldehyde is directly or indirectly involved in microglial activation during neuroinflammation.

4.1.3 Formaldehyde, Tau Hyperphosphorylation, and Microglia

Excessive exposure to FA also induces Tau protein aggregation and hyperphosphorylation in vitro and in vivo (Lu et al. 2013). The studies revealed that FA directly induced Tau aggregation and phosphorylation to form NFTs by activating the GSK/PP2A pathway (He et al. 2017; Lu et al. 2013; Nie et al. 2007a, b). Special attention needed to pay is that age-related FA could promote Tau hyperphosphorylation and inhibit NMDA-R to directly cause cognitive decline (Ai et al. 2019).

In addition, soluble hyperphosphorylated Tau is considered to drive the phenotypic change of microglia, causing defect of immunosurveillance function and facilitating disease progression through the formation of NFTs (Sanchez-Mejias et al. 2016). The investigation validated the Tau-induced microglial activation exist in mouse models of tauopathy, in which the mark is the upregulation of DAM-associated genes, including phagocytic and inflammatory modules (Wes et al. 2014). Both in cell culture and in healthy mouse brains, Tau fibrils are internalized by microglia, which support the previous results of upregulation of phagocytic genes (Bolos et al. 2016). Tau-mediated microglial activation is closely related to the activation of complement system by Tau fibrils through classical and alternative pathways (Wes et al. 2014). The studies indicated that Tau accumulation precedes the presence of active microglia cells in experimental AD models (Hopp et al. 2018; Yoshiyama et al. 2007). But other research found that the emergence of dystrophic microglia precedes the development of Tau pathology (Tischer et al. 2016). Activated microglia could also modified Tau activity by post-translational changes. Pro-inflammatory cytokines such as IL-1 and IL-6 that are generated by active microglia cause Tau phosphorylation (Wes et al. 2014). So it is unclear about their coactions, in which microglial inflammation plays a role in aggravating Tau aggregation and dissemination or on the contrary. However, microglia associated with Tau pathology show morphological degeneration in human brains, suggesting impaired function (Alzheimer’s Disease 2016; Streit et al. 2009). These pernicious changes are deemed to result from microglial senescence or chronic amyloid poisoning (Streit et al. 2018). Moreover, Aβ could exacerbate Tau pathology in synergy with microglia in the context of AD pathology (Felsky et al. 2019). In consideration of the complex interconnections among microglia, Aβ, and Tau, the communications among these units generate the positive feedback in the inflammatory environment of AD, causing a disordered and self-amplified inflammatory response (Wang et al. 2023). The relationship among FA, Tau hyperphosphorylation, and microglia activation was shown in Fig. 12.1.

4.2 Formaldehyde Disrupts BBB Leading to Neuroinflammation

It has been reported that microglia have little effect on BBB integrity under physiological conditions (Elmore et al. 2014), whereas microglial activation leads to BBB disruption during systemic inflammation or ischemic stroke (Haruwaka et al. 2019). Microglial activation precedes BBB disruption and cellular infiltrates in the brain tissues of multiple sclerosis patients (Yu et al. 2022). Both microglial activation and increased BBB permeability have been observed in cerebral small vessel diseases, but these are spatially distinct processes (Walsh et al. 2021). Astrocytes are glial cells with a characteristic anatomical location covering the endothelial cells of the BBB. They engage in neurovascular coupling, the integrity maintenance of the BBB, the regulation of blood flow, and the maintenance of synaptic homeostasis (Patabendige et al. 2021). Under physiological conditions, perivascular astrocytic end-feet are not tightly sealed (Pivoriūnas and Verkhratsky 2021). Conversely, it is characterized by BBB disruption and leukocyte infiltration into the CNS; end-feet of reactive astrocytes tighten the border to limit brain infiltration of peripheral immunocyte in response to inflammatory cues (Colombo and Farina 2016). Astrocytes could attenuate plaque formation through Aβ clearance, consequently exerting neuroprotective functions in AD (Joly-Amado et al. 2020). Astrocytes also express matrix metalloproteinases MMP-2 and MMP-9, which degrade both monomeric and fibrillar β-amyloid. In addition, extracellular proteins such as α1-antichymotrypsin (ACT), ApoJ/Clusterin, and α2-macroglobulin (α2-M), produced by astrocytes have the potential to clear Aβ (Ries and Sastre 2016). These data suggest that astrocytes more likely participate in β-amyloid clearance and elimination by different mechanisms. On the contrary, astrocytes are induced by Aβ, activated microglia, or noxious stimuli. Activated microglia could induce specific astrocyte-activating signals, which include TNF-α, IL-1α, and C1q. These signals, in turn, cleave APP by activating β-secretase and γ-secretase activity, and stimulate astrocytes to generate β-amyloid. Therefore, inflammatory stimulation of astrocytes can induce increased expression of β-site APP-cleaving enzyme (BACE1), APP, and β-secretase, implying a feed-forward mechanism of astrocytic Aβ production (Monterey et al. 2021). Similar evidences also revealed that a series of genes associated with AD including apolipoprotein E (APOE), Fermitin family member 2 (FERMT2), and Clusterin (CLU) are predominantly expressed by astrocytes (Liddelow et al. 2017).

FA is capable of penetrating through the BBB, with the degree of permeability relating to the concentration of FA in blood (Shcherbakova et al. 1986). It causes cell death and damage in brain regions, particularly the cells in the hippocampus, the loss of which leads to memory loss and subsequent cognitive dysfunction (Tong et al. 2013; Tsukahara et al. 2006). EB staining accumulation in the brain is a simple and reliable technique to assess the permeability of BBB (Manaenko et al. 2011). ZO-1 is a key protein associated with tight junctions (TJ) of microvascular endothelial cells, which is the foundation for complete structure of BBB (Nakagawa et al. 2009). They both evaluate the permeability of the BBB. Exposure to FA induced significant accumulation of EB in the mouse brain, and decreased the ZO-1expression, indicating the deteriorated permeability of the BBB. We have discussed earlier that microglia are activated in AD with the upregulated expression of Iba1. Zhao et al. (2024) used Iba1 as a marker to investigate the activation of microglia following intraperitoneal FA injection in C57BL/6 mice for four weeks. The results showed that FA injection significantly increased the number of activated microglia. Both immunohistochemical analysis and claudin 5 assay revealed that FA injection reduced claudin 5 levels and compromised the integrity of the blood–brain barrier (BBB). Astrocytes are essential for BBB integrity, and are important abundant cells in the CNS. GFAP expression is enhanced when significant transformation of astrocytes occurs after brain injury or disease. BBB repair may reduce the pathology of Aβ, P-Tau, and neuroinflammation. As shown in Fig. 12.1, formaldehyde could disrupt BBB integrity, activate microglia and astrocytes with enhanced expression of Iba1 and GFAP, followed by the elevated levels of inflammatory factors. In fact, it is still to clarify whether FA can activate the glia cells directly (Liu et al. 2018). Another pathway is that BBB permeability alteration caused by FA facilitates the migration of inflammatory cells and molecules into the brain, subsequently activating microglia and astrocytes to promote AD pathology. Thus, whether FA penetrates through the BBB and directly activates microglia and astrocytes, thereby inducing neuroinflammation, or inflammatory factors migrate from the circulatory system to the brain and activate glial cells, thereby causing neuroinflammation, remains to be elucidated.

5 Conclusion

In recent years, the role of neuroinflammation in the pathogenesis of AD has remained controversial. Some researchers think that the existence of peripheral inflammation may predate the pathological development of AD, and microglia and astrocytes, immune cells in the CNS, could respond to peripheral inflammatory factors, further promoting the pathological process of AD (Uddin et al. 2022). A bidirectional Mendelian randomization (MR) was performed to examine the role of circulating inflammatory proteins associated with or induced by autoimmune disease in the relationship between inflammatory diseases and AD. In this study, no strong evidence was found to support the notion that common inflammatory biomarkers affecting both risk of AD and inflammatory diseases, suggesting that neuroinflammatory processes responsible for AD may be distinct from the mechanisms underlying other inflammatory diseases (Huang et al. 2023). In summary, the persistence of this controversy over the years is largely due to widely accepted notion that the brain is isolated from the peripheral immune system. Since the twentieth century, several reports have revealed the negative impact of the immune response in the CNS. The studies focusing on neuroinflammatory diseases observed the presence of adaptive immune cells even in the CNS of healthy mammals (Hickey et al. 1991, 1992). It is now accepted that the lifelong formation of new neurons is supported by adaptive immune cells, whereas uncontrolled immune responses, such as those occurring during inflammation, impair neurogenesis (Castellani et al. 2023). In this chapter, as an inflammation-inducing factor, FA contributes to the onset of neuroinflammation through inducing Aβ deposits, Tau hyperphosphorylation, and BBB disruption which activates microglia, astroglia, and their cytokines and chemokines leading to the release. As shown in Fig. 12.1, formaldehyde induces amyloid beta deposition, elicits Tau hyperphosphorylation, and alters the blood–brain barrier (BBB) permeability, activating microglia and astrocytes and releasing cytokines and chemokines in neuroinflammation (Mata-Martínez et al. 2022; Monterey et al. 2021; Zhao et al. 2021; Felsky et al. 2019; Horváth et al. 2018; Liu et al. 2018; Streit et al. 2018; Corrigan et al. 2016; Wes et al. 2014; Lu et al. 2013; Michelucci et al. 2009). However, besides these pathways, FA participating in neuroinflammation through other pathways and the mechanisms involved in neuroinflammation are still worth further studying.

Acknowledgments

This project was supported by National Natural Science Foundation of China Joint Fund for Regional Innovation Development Project (no. U23A20522). Besides, the grants supporting this project are exhibited in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_13

13. Formaldehyde in Stroke and Vascular Dementia

Yalan Di¹, Shirui Huo², Ying Liu², Zhiqian Tong1, 3, Yan Wei⁴ and Rongqiao He4  

(1)

Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China

(2)

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China

(3)

Center for Cognitive Disorders, Beijing Geriatric Hospital, Beijing, China

(4)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) represents a significant contributor to morbidity and mortality globally following stroke events. To date, extensive research has been conducted on vascular dementia (VaD) and its underlying mechanisms. However, the potential influence of endogenous formaldehyde on VaD has garnered considerable attention among researchers. This chapter delineates the role of formaldehyde in stroke, its involvement in protein cross-linking during blood coagulation, and its impact on lipid peroxidation and atherosclerosis. Furthermore, we explore the correlation between formaldehyde-induced cognitive impairment and VaD, along with alterations in endogenous formaldehyde levels among stroke and VaD patients. Additionally, we review the plausible mechanisms through which formaldehyde and formic acid exert effects on stroke and cognitive decline. Hypertension and oxidative stress stimulate the expression of semicarbazide-sensitive amine oxidase (SSAO) in blood vessels, resulting in excessive formaldehyde production. Elevated levels of formaldehyde (or formic acid) may represent a potential risk factor for stroke in patients with hypertension and hyperlipidemia, potentially precipitating the development of VaD. Collectively, the findings from existing research suggest that formaldehyde and formic acid could emerge as biomarkers and viable therapeutic targets for the clinical management of stroke and VaD.

Keywords

StrokeVascular dementiaOxidative stressHypertensionAtherosclerosisSemicarbazide-sensitive amine oxidase (SSAO)HyperlipidemiaBlood vessel damage

Abbreviations

A

ACE

Angiotensin-converting enzyme

AD

Alzheimer’s disease

AT1R

Angiotensin II type 1 receptor

D

DPC

DNA-protein cross-links

H

H₂O₂

Hydrogen peroxide

L

LIMA

Left internal mammary artery

M

M1dG

Malondialdehyde-deoxyguanosine

M2FA

Malondialdehyde-formaldehyde

MDA

Malondialdehyde

N

NH₃

Ammonia

P

PSCID

Post-stroke cognitive impairment and dementia

R

ROS

Reactive oxygen species

S

SSAO

Semicarbazide-sensitive amine oxidase

V

VaD

Vascular dementia

VAP-1

Vascular adhesion protein-1

VSMCs

Vascular smooth muscle cells

1 Introduction

Vascular dementia (VaD) stands as another prevalent form of dementia alongside Alzheimer’s disease (AD), accounting for approximately 15–20% of dementia cases in Europe, with estimates rising to about 30% in Asia (Jhoo et al. 2008; Chan et al. 2013; Rizzi et al. 2014) and in developing nations (Kalaria et al. 2008). Notably, among hospitalized patients in China, VaD constitutes a striking 51.27% of dementia cases (Wang et al. 2023a, b). However, these two disorders frequently coexist, with “pure” instances of AD or VaD being relatively uncommon, despite the clinical and research community continuing to view them as distinct entities (Xi and Tao 2015). Unlike AD, there are no approved therapies specifically tailored for VaD, aside from medications targeting underlying vascular disorders. For instance, the compound Chinese medicine Sailuotong has been proposed as a promising treatment for VaD (Jia et al. 2018). While a connection between vascular and degenerative dementia pathologies has been established, the underlying mechanistic link between them remains elusive (O’Brien and Thomas 2015). It is now recognized that multi-infarct dementia represents just one of several potential causes of VaD, and pathological studies involving large cohorts have demonstrated that subcortical vascular diseases are responsible for the majority of VaD cases (Roman et al. 2002).

Stroke, a brain injury resulting from interrupted blood supply, manifests as a complication of hypertension and atherosclerosis (Sierra et al. 2011). Hypertension and hyperlipidemia are recognized as primary risk factors for stroke (Tu et al. 2010; Kim et al. 2012; Pandian et al. 2018; Campbell and Khatri 2020). Hypertension exacerbates the risk of atherosclerosis, thereby increasing the likelihood of stroke-related complications (Staub 1960). During a stroke, brain tissue rapidly deteriorates due to the absence of blood-supplied oxygen and nutrients, leading to sudden brain dysfunction. Intriguingly, urine formaldehyde concentrations in stroke patients have been noted to elevate significantly (Tong et al. 2017). Individuals accidentally ingesting methanol orally or exposed to formaldehyde may exhibit pathomorphological damages such as brain edema and submucosal vascular congestion (Zhang et al. 2022).

Formaldehyde in the body originates from both endogenous and exogenous sources. Creatine metabolism represents one pathway for endogenous formaldehyde production in humans (Nasseri and Jafari 2016). Methenamine and acetamide undergo oxidative deamination, catalyzed by semicarbazide-sensitive amine oxidase (SSAO), to produce formaldehyde, hydrogen peroxide (H₂O₂), and ammonia (NH₃) (Foot et al. 2022). Another source of endogenous formaldehyde is the one-carbon metabolism of specific amino acids, including methionine, serine, histidine, glycine, and arginine (Li et al. 2021). Endogenous formaldehyde production, catalyzed by serine hydroxy methyltransferase, primarily occurs within mitochondria (Geller and Kotb 1989; Zhao et al. 2020). In the homocysteine cycle, methionine sulfoxide reacts with acetic anhydride to form an acetoxy derivative of methionine, which hydrolyzes in hydrochloric acid to produce homocysteine, formaldehyde, and acetic acid (Oae et al. 1963; Kalász 2003). Formaldehyde is produced intermittently under both normal physiological and pathological conditions. Enzymes oxidize formaldehyde to formic acid, which is further metabolized into carbon dioxide in the human body. Most inhaled formaldehyde is processed in the cells lining the nose, mouth, throat, and airways (https://​www.​cancer.​org/​cancer/​risk-prevention/​chemicals/​formaldehyde.​html). In this chapter, we delve into the relationship between vascular dementia and endogenous formaldehyde.

2 Formaldehyde and Stroke

2.1 Stroke as a Prerequisite for Vascular Dementia

Stroke stands as a prominent precipitating factor in the global prevalence of VaD, with post-stroke cognitive impairment (PSCI) playing a pivotal role. The clinical pathological hallmark of VaD is the manifestation of memory decline following a stroke (Renjen et al. 2015). PSCI arises secondary to ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage (Kalaria et al. 2016; Rost et al. 2021, 2022). Yu proposed a hypothesis that SSAO, an enzyme involved in formaldehyde production, to both AD and VaD (Yu 2001). Preliminary data from our collaboration with the Beijing Hospital of the Elderly, although unpublished, indicate a marked elevation in urine formaldehyde levels among VaD patients compared to the control group, hinting at a potential connection between stroke and formaldehyde metabolism.

A history of stroke is the prerequisite for the diagnosis of VaD. Ischemic stroke results from blood infarction with thrombus. In 2017, we conducted a study to measure endogenous formaldehyde levels in stroke patients, using age-matched healthy participants as control group (Tong et al. 2017). Our findings revealed significantly higher urine formaldehyde level in stroke patients compared to the healthy controls. We will discuss the relationship between formaldehyde and stroke from four aspects: First, formaldehyde acts as a cross-linker that polymerizes serum proteins, thereby potentially disrupting blood circulation. Second, atherosclerosis is a key pathogenic factor in stroke (Sierra et al. 2011). Third, lipid peroxidation plays an important role in the progression of atherosclerosis. Lastly, hypertension not only elevates the risk of atherosclerosis, but also increases the chances of developing associated complications.

2.2 Formaldehyde-Mediated Protein Coagulation Through Cross-Linking

Formaldehyde is well-recognized for its role as a cross-linking agent, capable of polymerizing biomacromolecules such as proteins and potentially precipitating protein aggregation. Notably, formaldehyde has been shown to significantly induce Tau polymerization not only in phosphate buffer solution (pH 7.2) (Nie et al. 2007a) but also within SH-SY5Y and HEK 293 T cells (Nie et al. 2007b). This ability to promote Tau aggregation both in vitro and in vivo underscores formaldehyde’s neurotoxicity to neural cells. Additionally, formaldehyde reacts with blood proteins involved in coagulation, potentially leading to blood infarction. Zhang et al. proposed a hypothesis based on the pathological characteristics of a case involving a fatal oral ingestion of formaldehyde suggesting that the aldehyde’s cross-linking properties cause rapid fixation of blood in tissues, resulting in acute circulatory disturbance (Zhang et al. 2022).

As an intermediate product of methanol metabolism, formaldehyde plays a significant role in methanol intoxication. A clinical study by (Cejnar et al. 2022) identified proteins involved in blood coagulation as key players in methanol poisoning. Consistent with this, a case report (Owolabi et al. 2020) demonstrated that methanol poisoning can induce stroke. Our previous research revealed that the concentration of formic acid (a metabolite of formaldehyde) in the blood of stroke patients is elevated compared to that of a normal control group, possibly due to accelerated formaldehyde production and metabolism into formic acid in these patients (Di et al. 2022). Collectively, these clinical and experimental evidences suggest that formaldehyde may pose a risk factor for stroke by disrupting the coagulation process.

2.3 Lipid Peroxidation and Atherosclerosis

Exposure to formaldehyde at levels detrimental to health can lead to oxidative stress and lipid peroxidation. Extensive research has demonstrated a close correlation between lipid peroxidation and atherosclerosis (Esterbauer et al. 1993; Shao and Heinecke 2009). Furthermore, elevated plasma levels of lipids and glucose are linked to endothelial dysfunction during the early stages of type 2 diabetes development (Okon et al. 2007). Studies have shown that increased levels of 15-F2t-isoprostane, a biomarker of lipid oxidation, in individuals repeatedly exposed to formaldehyde, such as nurses (Bellisario et al. 2016) and Italian industry workers (Bono et al. 2019). Similarly, workers regularly exposed to formaldehyde in a plastic laminate plant exhibited heightened levels of malondialdehyde-deoxyguanosine (M1dG) adduct, a biomarker of oxidative stress and lipid peroxidation (Bono et al. 2016). Aldehydes resulting from lipid peroxidation are implicated in various oxidative stress-related pathologies, including atherosclerosis, neurodegenerative disorders, and inflammatory processes (Shibamoto 2006; Rodríguez-Zavala et al. 2019). Evidence suggests that lipid oxidation products influence atherosclerosis through inflammatory pathways, with formaldehyde potentially serving as an inflammatory trigger.

In the presence of formaldehyde exposure, lipid peroxidation produces malondialdehyde (MDA) (Mason et al. 1972). Mason et al. (1972) observed the generation of lipid peroxides and MDA during the isolation of phagocytic vesicles from activated alveolar macrophages. Compared to control groups, rats exposed to formaldehyde exhibited significantly elevated MDA levels (Zhou et al. 2011; Wang et al. 2013). MDA, produced during the oxidative degradation of polyunsaturated lipids, serves as a biomarker for oxidative stress (Qiang et al. 2014). In humans, acute exposure to formaldehyde has been associated with an increase in MDA, a biomarker of lipid peroxidation, among female adults (Augenreich et al. 2020). MDA and other toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal, are often considered in the progression of atherosclerosis (Leong 2021). During further oxidative degradation, MDA breaks down to release formaldehyde (Li et al. 2008, 2010). The reaction between formaldehyde and MDA forms malondialdehyde-formaldehyde (M2FA)-lysine adducts, contributing to vascular diseases, including atherosclerosis (Nakamura et al. 2017).

2.4 Formaldehyde and Atherosclerosis

Stroke primarily stems from atherosclerosis, prompting us to delve into the interplay between endogenous formaldehyde and this critical condition. Atherosclerosis often arises due to damage to vascular endothelial cells. Formaldehyde, even at low concentrations ranging from 0.05 to 0.1 mM, synergizes with H₂O₂ to impair endothelial cells, thereby emerging as a plausible contributor to the predisposition towards atherosclerosis (Lin et al. 2005). In the presence of lysine, formaldehyde reacts with two molecules of MDA to yield a highly stable adduct of the 1,4-dihydropyridine type, known as M2FA-Lys. The significance of this adduct is as a key mediator in the progression of atherosclerosis (Chen et al. 2024). Additionally, high cholesterol levels, oxidative stress, inflammatory factors, and recurrent vascular endothelial injuries are recognized as risk factors for atherosclerosis. Endogenous formaldehyde, due to its highly reactive and cytotoxic nature, further exacerbates susceptibility to atherosclerosis, particularly through SSAO-mediated methylamine metabolism (Oae et al. 1963; Precious et al. 1988).

SSAO catalyzes the oxidation of methylamine and other monoamines, generating substantial amounts of formaldehyde. This formaldehyde subsequently induces intra- and intermolecular cross-linking between proteins, as well as between proteins and nucleic acids (RNA/DNA). Such cross-linking, particularly in the basal membranes of blood vessels, can lead to membrane deterioration (Yu and Deng 1998). Exposure to formaldehyde enhances pro-inflammatory responses in murine macrophages, facilitated through glycolysis and HIF-1α signaling pathways, as evidenced by studies conducted by Lino-dos-Santos-Franco et al. (2011) and Ma et al. (2021). Inhalation of formaldehyde boosts the production of reactive oxygen species (ROS) via protein nitration, disrupting the physiological balance between oxidant and antioxidant enzymes and damaging blood vessel epithelia. This imbalance suggests that ROS may exacerbate formaldehyde-induced cellular damage. Consequently, modulating oxidant pathways may mitigate the detrimental effects of formaldehyde and positively regulate the inflammatory response.

2.5 Formaldehyde and Hypertension

2.5.1 SSAO: An Enzyme Producing Formaldehyde

SSAO, also referred to as vascular adhesion protein-1 (VAP-1), exhibits robust expression in endothelial cells, smooth muscle cells, and adipocytes. As a member of the primary amine oxidase family, SSAO contains divalent copper ions and demonstrates particular sensitivity to amino urea in the presence of 6-hydroxydopaquinone. Leveraging 6-hydroxydopamine as a cofactor, SSAO comprises a short cytoplasmic chain, a distinct transmembrane segment, and a highly glycosylated extracellular catalytic domain housing the active site. This active site is essential for enzymatic activity, incorporating 6-hydroxydopaquinone and copper ions. SSAO catalyzes the deamination of its primary endogenous substrates, methylamine and acetamidine, into formaldehyde both in vivo and in vitro, accompanied by the co-production of H₂O₂ and NH₃ (Boor et al. 1992; Yu et al. 2003; Lin et al. 2005; Foot et al. 2022). Furthermore, VAP-1/SSAO plays a pivotal role in regulating the adhesion and exudation of leukocytes within and from blood vessels (Li et al. 2021).

2.5.2 The Relation Between Formaldehyde and Hypertension

Let us delve into the role that formaldehyde plays in hypertension, considering the intimate association between its occurrence and the progression of atherosclerosis. Cole’s investigation in 1974 shed light on formaldehyde-induced ocular hypertension and the mitigating effects of polyphloretin phosphate and (+)-catechin on this condition. Building upon this, a recent study revealed that air pollution stemming from fossil fuels and combustion, inclusive of formaldehyde, is correlated with systemic hypertension (Xu et al. 2022). Furthermore, as previously discussed, the metabolic derivative of formaldehyde, formic acid, has been implicated in hypertension-related hemorrhage in both hSSAOTG mice and humans (Di et al. 2022). This underscores that hypertension is intricately tied not only to formaldehyde but also to its metabolite, formate. A contemporary study conducted on C57BL/6 male mice exposed to varying concentrations of formaldehyde demonstrated that this compound elevates blood pressure by fostering and activating the angiotensin-converting enzyme (ACE)/angiotensin II type 1 receptor (AT1R) axis (Wang et al. 2023a, b). Additionally, an earlier study reported significantly elevated artery pressure in SMP8-SSAO transgenic mice compared to control groups. These transgenic mice, with overexpressed SSAO, also exhibited disrupted elastin architecture in their large arteries (Göktürk et al. 2003). Collectively, these findings hint at a potential direct or indirect role for formaldehyde in the onset and exacerbation of hypertension.

2.5.3 Formaldehyde and Blood Damage

Chronic exposure to formaldehyde, even at low concentrations, holds the potential to impair the cardiovascular system, ultimately influencing blood pressure regulation in humans. A recent study has established a positive correlation between blood pressure and the concentration of formaldehyde in the blood (Lv et al. 2022). VAP-1, an inflammation-inducible adhesion molecule present in endothelial cells (Salmi et al. 1993), also functions as a monoamine oxidase in the smooth muscle of blood vessels. When expressed in vascular cell lines, endothelial VAP-1 interacts with granulocytes, lymphocytes, and monocytes (Solé and Unzeta 2011), potentially causing endothelial cell injury and exacerbating hypertension. Research has shown that patients with hypertension exhibit significant changes in their blood vessel walls compared to normotensive individuals (Touyz 2003; Rubio-Ruiz et al. 2014). These alterations affect both endothelial cells and vascular smooth muscle cells (VSMCs), leading to damage of the blood vessels. This vascular damage may contribute to elevated blood pressure (Hughes and Schachter 1994). Furthermore, available evidence indicates that hypertension and oxidative stress activate SSAO. The formaldehyde produced as a result of SSAO activation further damages blood vessels, perpetuating a vicious cycle that exacerbates hypertension.

3 Cell Damage in Blood Vessels

3.1 Cytotoxicity of Reactive Carbonyl Compounds

Formaldehyde, a reactive carbonyl compound (RCC), is produced in endothelial cells, smooth muscle cells, adipocytes, and pericytes due to the predominant expression of VAP-1 in these cell types (Danielli et al. 2022). SSAO exists not only in membrane-bound form in most tissues but also in free form in mammalian plasma (Zhang et al. 2010; Gharaghani et al. 2013; Jargaud et al. 2021). As a member of the SSAO family, VAP-1 catalyzes the oxidation of primary amines, producing ammonium and H₂O₂, along with RCCs such as formaldehyde and methylglyoxal. Fibrinogen, a crucial protein in plasma coagulation, deposits on blood vessel walls and plays a vital role in the pathology of atherosclerosis. RCCs induce fibrinogen aggregation, suppressing fibrinogenesis and plasma coagulation, indicating that aggregated fibrinogen may accumulate in blood vessels (Xu et al. 2012). Additionally, RCCs can damage endothelial cells in the human brain and disrupt the blood-brain barrier (Toth et al. 2014).

3.2 Formaldehyde and Vascular Smooth Muscle Cells

Vascular smooth muscle cells (VSMCs) and endothelial cells contain abundant formaldehyde-producing enzymes (VAP-1/SSAO). These cells are susceptible to damage due to the potential toxicity of formaldehyde generated by SSAO catalysis, leading to apoptosis (programmed cell death) of VSMCs (Hernandez et al. 2006; Zhang et al. 2021). In VSMCs, VAP-1 is localized on the cell surface, undergoes N-linked post-translational modifications, and exists in trimeric forms (Jaakkola et al. 1999). As a monoamine oxidase in VSMCs, VAP-1 accounts for most SSAO activity in humans and plays a key role in vasculopathies (Salmi et al. 1993). Formaldehyde, methylamine, and H₂O₂ can induce relaxation of the left internal mammary artery (LIMA) via VSMC hyperpolarization and K⁺ channel activation (Conklin et al. 2004). Studies have shown that the LC₅₀ for formaldehyde in rat VSMCs is 1 × 10⁻⁴ M (Langford et al. 2001), while 0.5 mM formaldehyde causes near-complete loss of A7r5 cell viability (Hernandez et al. 2006). Recently, Manasieva et al. (2023) identified SSAO as a key mediator of ROS formation and cytotoxicity in cultured VSMCs. This finding further suggests that SSAO activity is potentially linked to early atherosclerosis through oxidative stress and vascular damage. In summary, VAP-1/SSAO generates formaldehyde and ROS, leading to VSMC cytotoxicity and potentially contributing to early atherosclerosis via oxidative stress and vascular damage (Manasieva et al. 2023).

3.3 Formaldehyde and Endothelial Cells

VAP-1 exists in both monomeric and dimeric forms within endothelial cells (Salmi and Jalkanen 1996). While endogenous methylamine at normal level exhibits nontoxic to endothelial cells, the formaldehyde produced through SSAO-catalyzed oxidation of methylamine is toxic and results in localized damage to these cells. It is crucial to note that formaldehyde alone does not suffice to cause cellular damage; other intravascular components likely contribute to these reactions (Yu and Zuo 1996). First, formaldehyde progressively induces a significant increase in DNA-protein cross-links (DPCs) in endothelial cells over time, exacerbating cellular injury during the aging process. This potential injury stems from the inadequate formaldehyde clearance mechanisms in the bloodstream, as highlighted by Lin et al. (2005). Second, formaldehyde derived from the deamination of methylamine (substrate), particularly due to persistently elevated SSAO levels in the blood, can induce chronic stress, repeatedly compromising endothelial cell health. Third, increased methylamine deamination also elevates H₂O₂ levels, primarily contributing to oxidative stress (Lum and Roebuck 2001). Furthermore, excessive formaldehyde can induce apoptosis in endothelial, epithelial, and other cell types while inhibiting cellular repair mechanisms by suppressing cell proliferation, as demonstrated by Tyihak et al. (2001) and Manasieva et al. (2023).

3.4 Oxidative Stress Induces Elevated Levels of Formaldehyde

Stroke is invariably accompanied by oxidative stress and ROS production, leading to blood vessels damage and neural cell death (Mao et al. 2022). Notably, oxidative stress is a consequence of the pathophysiological process associated with ischemic stroke (Orellana-Urzúa et al. 2020). Utilizing a formaldehyde fluorescent probe, Chen et al. (2017) observed a significant increase in endogenous formaldehyde levels in murine neuroblastoma 2a cells (N2a) under oxidative stress conditions. Similarly, formaldehyde levels were significantly elevated (P < 0.01) in the brains of rats subjected to chronic cerebral hypoperfusion compared to the sham group. Comparable results were also observed in blood endothelial cell line (bEnd.3) under oxidative stress conditions (Chen et al. 2017). The excessive formaldehyde presenting during oxidative stress states at least partially contributes to the damage of blood and neural cells.

4 Formaldehyde and Cognitive Impairment

Early in the 1980s, researchers discovered that workers frequently exposed to formaldehyde-laden working environments were more prone to experiencing memory decline (Kilburn et al. 1987). Inhaling lower concentrations of formaldehyde does not markedly impair learning and memory abilities. To further investigate the impact of inhaled formaldehyde on cognitive functions, scholars conducted experiments on mice by exposing them to either 1 mg/m³ or 3 mg/m³ of gaseous formaldehyde, and their performance was monitored in Morris water maze. The results revealed a significant decline in water maze performance in the 3 mg/m³ group compared with control (P < 0.01). This finding indicates that high levels of formaldehyde can impair learning and memory abilities (Lu et al. 2008). French epidemiologists have reported that individuals exposed to formaldehyde during their professional life are at a heightened risk of global cognitive impairment and deficits for all cognitive domains explored. The duration of exposure and the cumulative life-time dose were positively correlated with the severity of cognitive impairment, demonstrating a dose–response relationship. The extent of the memory decline was found to be dependent on the duration of exposure. Similarly, nail salons workers, who are frequently exposed to products containing formaldehyde, also suffer from memory impairment and mild neurotoxicity (LoSasso et al. 2002). Experimental studies on mice have shown that exposure to formaldehyde can impair cognitive abilities, such as memory and learning ability, through oxidative stress mechanisms (Lu et al. 2008; Li et al. 2021). Those findings suggest a link between exposure to formaldehyde and its metabolite, formic acid, and the development of stroke and VaD.

As described by Letellier et al. (2022), formaldehyde-associated cognitive deficits may not be fully reversible over time, and individuals with recent exposure experience greater cognitive impairment. Their research emphasized the cognitive decline observed in a relatively young population after long-term formaldehyde exposure. The data indicated that formaldehyde-impaired cognitive function is relevant in both pre-stroke and post-stroke patients, particularly in cases where formaldehyde accumulates in the brain. Figure 13.1 illustrates a putative role for formaldehyde to play in VaD (Di et al. 2022; Yu and Deng 1998; Zhang et al. 2022; Nie et al. 2007a, b; Xu et al. 2012; Jaakkola et al. 1999, Lin et al. 2005). Hyperlipidemia resulting from metabolic dysfunction is a risk factor for atherosclerosis (Fischer et al. 2015). Atherosclerosis and hypertension damage blood vessels, creating a vicious cycle that exacerbates both conditions. Hypertension and oxidative stress stimulate the expression of SSAO in blood vessels, leading to increased levels of SSAO that may produce excessive formaldehyde. Abnormally high levels of formaldehyde may pose as a potential risk factor for stroke in individuals with hypertension and hyperlipidemia. Consequently, formaldehyde-induced vascular damage and stroke may contribute to the development of VaD. Additionally, formic acid, the primary toxic metabolite of formaldehyde, can cause high anion gap metabolic acidosis and brain lesions, including cell death (Atacan Yaşgüçlükal et al. 2022).

Fig. 13.1

A putative role for formaldehyde to play in VaD

5 Future Perspectives

In recent times, numerous scientists have devoted considerable effort to exploring the intricate relationship between formaldehyde and various diseases. However, despite these endeavors, in-depth re-examinations of formaldehyde’s role in the etiology of atherosclerosis, stroke, VaD, and AD remain relatively scant. A recent study, leveraging simultaneous fluorescence techniques, identified three pivotal indicators—formaldehyde, malondialdehyde, and monoamine oxidase A—as being significantly associated with ischemic stroke (Su et al. 2024). This discovery aligns with prior research suggesting that endogenous formaldehyde and formate could serve as predictors of cognitive impairment in post-stroke dementia (Tong et al. 2017). In light of these revelations, several laboratories have embarked on investigations aimed at developing preventive measures against formaldehyde exposure and potential treatments to mitigate its detrimental effects. Silibinin could ameliorate formaldehyde-induced cognitive impairment by inhibiting oxidative stress (Wei et al. 2022). Similarly, hydrogen sulfide (H₂S) has shown promise in alleviating formaldehyde-induced cognitive dysfunction, with the underlying mechanism involving the reduction of hippocampal oxidative damage and apoptosis, as well as the upregulation of hippocampal brain-derived neurotrophic factor (Li et al. 2020). Further insights into potential therapeutic agents for treating formaldehyde exposure and its associated cognitive impairments are detailed in Chap. 18.

Nonetheless, future investigations should prioritize addressing several critical topics: (1) Ascertaining the primary sources of endogenous formaldehyde and their relative impacts on brain function and pathology; (2) Elucidating the molecular mechanisms through which formaldehyde affects endothelial cells, smooth muscle cells, and pericytes, ultimately leading to vascular dysfunction; (3) Investigating the direct relationship between formaldehyde and stroke pathogenesis, extending beyond its role in atherosclerosis; (4) Exploring whether and how formaldehyde-induced vascular damage and stroke contribute to the development of VaD; and (5) Assessing the feasibility of targeting formaldehyde and formic acid levels or pathways for early detection, prevention, or treatment of stroke and VaD.

Acknowledgments

This project was supported by National Natural Science Foundation of China Joint Fund for Regional Innovation Development Project (no. U23A20522). Besides, the grants supporting this project are exhibited in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_14

14. Formaldehyde in Diabetes and Cognitive Impairment

Lixian Mou1, 2, 3 and Rongqiao He4  

(1)

Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China

(2)

Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, China

(3)

Academician (Expert) Workstation of Sichuan Province, Luzhou, China

(4)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high blood glucose levels that can cause structural and functional changes in multiple tissues and organs in the body, leading to various complications and seriously affecting human health. Epidemiological findings suggest that diabetic patients are at a greater risk of dementia, including Alzheimer’s disease (AD). Recent studies have demonstrated that increased endogenous formaldehyde (FA) levels can be generated in severe diseases such as DM and AD. Endogenous FA can be produced via oxidative deamination of methylamine catalyzed by semicarbazide-sensitive amine oxidase (SSAO) and is ubiquitous in fluids, tissues, and cells of the body. Meanwhile, SSAO activity has been clinically confirmed to be increased in DM and AD, and SSAO is predominantly located in the vascular smooth muscles, retina, kidney, and cartilage tissues. FA, as a cross-linking agent, is capable of causing high cytotoxicity toward endothelial cells. Moreover, FA plays a crucial role in exacerbating oxidative stress and advanced glycation. Thus, FA is a chronic risk factor for angiopathy, which is the leading cause of nephropathy, retinopathy, and encephalopathy (cognitive impairment) in DM. In this review, we briefly summarize the research progress of FA in diabetes and its related complications and further discuss the role of FA in cognitive impairment from DM to AD.

Keywords

FormaldehydeDiabetes mellitusCognitive impairmentAlzheimer’s diseaseSemicarbazide-sensitive amine oxidase

Abbreviations

A

Aβ

Amyloid-Beta

AD

Alzheimer’s disease

ADH

Alcohol dehydrogenase

AGEs

Advanced glycation end-products

ALDH2

Aldehyde dehydrogenase 2

AOD

Alcohol oxidase

APP/PS1

Amyloid precursor protein/presenilin 1

ATP

Adenosine triphosphate

B

BSA

Bovine serum albumin

C

CO

Carbon monoxide

CN

Copy number

D

DM

Diabetes mellitus

DNA

Deoxyribonucleic acid

F

FALDH

Formaldehyde dehydrogenase

G

GBM

Glomerular basal membrane

H

H₂O₂

Hydrogen peroxide

M

MDA

Malondialdehyde

MeOH

Methanol

MGO

Methylglyoxal

MMSE

Mini-Mental Status Exam

MMOp

Methane monooxygenase particulate

MMOs

Methane monooxygenase soluble

R

RAGE

Receptor for advanced glycation end-products

S

SSAO

Semicarbazide-sensitive amine oxidase

T

T2D

Type 2 diabetes

V

VOCs

Volatile organic compounds

1 Introduction

Diabetes mellitus (DM) has become a significant public health issue worldwide as its prevalence has increased sharply (Sun et al. 2022). The long-standing hyperglycemia of DM can cause vascular endothelial damage, leading to complications with high mortality and disability, clinically known as diabetic neuropathy, retinopathy, nephropathy, and atherosclerosis, respectively (Girach et al. 2006). Hyperglycemia is a risk factor in the progression of cognitive impairment, including Alzheimer’s disease (AD) and related dementia. That is, AD patients are more likely to develop from type 2 diabetes (T2D). Therefore, AD could be proposed as the brain-specific type of diabetes as type 3 diabetes (Ryan et al. 2006). Endothelial dysfunction, inflammation, protein glycation, oxidative stress, metabolic disruption, and several other pathways may be common biological mechanisms between DM and AD (Maniar et al. 2017; Tang et al. 2018).

As described previously, formaldehyde (FA) is capable of exacerbating advanced glycation in diabetes and thus increasing the complexity of protein cross-linking (Yu 1998). In this laboratory, diabetic patients with lower Mini-Mental Status Exam (MMSE) sores had higher FA levels in their hippocampi and urine than those in normal individuals, indicating that FA plays an important role in diabetes complications (Tong et al. 2011). Su et al. (2013) demonstrated that T2D patients suffer from not only glucose dysmetabolism but also ribose. Sequentially, ribose has active chemical properties and partially produces FA in solution under weak alkali conditions (Wang et al. 2019a, b). Furthermore, methylation and demethylation are involved in FA metabolism (Shi et al. 2004; Bou-Nader et al. 2021). Glycated bovine serum albumin (BSA) in the presence of ribose is able to induce demethylation of histones, leading to production of FA in SH-SY5Y cells (Xi et al. 2022). Thus, we proposed that long-standing hyperglycemia (including high levels of blood ribose) will lead to increased formation of endogenous FA and may be involved in developing DM and complications, especially cognitive impairment. For instance, Grönvall-Nordquist et al. found that FA-generating enzymes were expressed in diabetes patients (Grönvall-Nordquist et al. 2001). Higher levels of FA were detected in the cecum of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice compared to C57BL/6 J mice by detecting FA in the intestinal wall and contents. This result suggests that the intestines should contain methanol and formic acid in normal and abnormal mice (Liu et al. 2017). Moreover, it has been confirmed that some microbial groups in the human gut can metabolize methanol, as described in Chaps. 2 and 7. FA is cytotoxic and involved in different pathways in cells. First, many studies have proposed that endogenous FA can destroy the structure and function of mitochondria and eventually lead to cell death (Hernandez et al. 2006; Ai et al. 2019). Furthermore, the addition of FA to bEnd.3 cells and N2a cells markedly induced the production of reactive oxygen species, which could damage those cells (Chen et al. 2017). In fact, it is well known that FA dysregulates mitochondrial DNA damage and repair in mammalian cells (Nadalutti et al. 2021). Zhu emphasized the importance of methanol-formaldehyde-formic acid metabolic pathways in diabetes and summarized some biochemical mechanisms underlying the pathogenesis of diabetic retinopathy and other diabetic complications (Zhu 2022). Interestingly, the accumulation of FA can also induce chronic hyperglycemia in diabetes, which leads to cognitive decline (Tan et al. 2018). According to these studies, increased levels of FA in humans may contribute to the pathogenesis and development of DM and AD. Here, we review the mechanism of the formation of endogenous FA, with a focus on the potential pathophysiological mechanism of FA in diabetic complications, and further discuss the role of FA in the cognitive impairment from DM to AD.

2 Metabolic Pathways of FA in Diabetes Mellitus

The FA burden in the human body is generated in endogenous and exogenous ways. Endogenous FA is a by-product of aldehyde metabolism. There are different primary sources, such as methylamine deamination, oxidation of methanol, and histone demethylation (Wang et al. 2019a, b). Due to the continuous action of FA-metabolizing enzymes through multiple metabolic pathways, FA does not usually accumulate to a very high concentration in the body. According to Heck et al. (Heck et al. 1982), FA concentrations within normal human blood are generally 0.08 mM and are 0.2–0.4 mM in brain tissue. However, a surprising finding is that the serum lacks FA dehydrogenase. Thus, FA cannot be metabolized in blood until transported into erythrocytes, and this is an interesting finding regarding FA-induced toxicity to blood vessels (Yu 1998). Furthermore, it is well known that semicarbazide-sensitive amine oxidase (SSAO) is an enzyme that promotes the deamination of methylamine and generates FA, which is one of the most common metabolic pathways of endogenous FA (Yu et al. 2000). SSAO occurs in soluble or membrane-bound forms, primarily in endothelial cells and smooth muscle cells in the body. It is noteworthy that serum SSAO levels are relatively stable among healthy adults but are increased in various pathological conditions, such as heart failure, chronic kidney injury, DM, and AD (Valente et al. 2012; Qiang et al. 2014), which provide an intracellular environment to easily generate more FA in DM patients. Furthermore, various environmental factors contribute to exogenous FA, including construction materials, agricultural fertilizers, cleaning agents, and so on (Wang et al. 2019a, b).

Carbohydrates, including glucose, are decomposed to methane and then produce methanol and FA in human intestines (Zhang et al. 2022). Since diabetes features hyperglycemia, changes in glucose metabolism in the gut microbiota to produce methanol are one of the important sources for FA in addition to other sources. Hydrogen/methane production in intestines based on glucose intake has been used to test the changes in intestinal flora for diabetic patients (Rezaie et al. 2017; Fialho et al. 2018). A biochemical methanol gas sensor (MeOH Bio-Sniffer) is also employed to detect methanol in breath as a noninvasive assessment of the intestinal flora (Toma et al. 2021). Wang et al. (2021) observed changes in the metabolism of methanol in the intestinal flora of T2D patients even though they were normoglycemic individuals. Analyzing volatile organic compounds (VOCs) serves as a noninvasive method for T2D patients. Lourenço et al. (2019) found statistically significant differences in VOCs between Cushing’s mice/wild-type littermates in longitudinal differences mainly attributed to methanol, ethanol, and acetone. As described by Atkinson et al. (2018), individuals with low salivary α-amylase gene copy number displayed over sixfold higher breath methane levels in the fasting state and after starch ingestion than high copy number (CN) individuals (P = 0.001). These data demonstrate that the source of FA for diabetes is methane produced from intestinal flora during the decomposition of carbohydrates, especially high levels of sugars. Decomposition of carbohydrates (fruits and vegetables) produces many compounds in the intestines, including methane, which is converted to methanol followed by formaldehyde and formic acid (Zhang et al. 2022). The pectin/PME complex is believed to be a source of methanol (Shindyapina et al. 2014; Dorokhov et al. 2015) The authors fed rhesus monkeys with methanol and observed increased formaldehyde levels in brain and urine (Yang et al. 2014a, b). In this laboratory, we have detected formaldehyde in feces of APP/PS1 mice in the cecum (Liu et al. 2017) and in humans. Those APP/PS1 mice suffered from high levels of formaldehyde in their intestines (see Chap. 7). Intraperitoneal injection of formaldehyde increases endogenous formaldehyde levels (Lu et al. 2013). All these data indicate that methanol and formaldehyde can be absorbed from intestines into blood and then cells (Fig. 14.1).

Fig. 14.1

Scheme for the source of methanol and formaldehyde from gut microbiota. ADH alcohol dehydrogenase (EC 1.1.1.1), ADH3 alcohol dehydrogenase 3 (EC 1.2.1.1), ALDH2 aldehyde dehydrogenase 2 (EC 1.2.1.3), AOD alcohol oxidase (EC 1.1.3.13), FALDH formaldehyde dehydrogenase (EC 1.2.1.1), MMOp methane monooxygenase (particulate) (EC 1.14.18.3), MMOs methane monooxygenase (soluble) (EC 1.14.13.25) and. PME pectin methylesterase (EC 3.1.1.11)

Formaldehyde can interact with monoamines and amides to form Schiff bases and then form a methylene bridge. It can also form irreversible covalent cross-linking complexes with essential biomolecules such as protein and DNA, thus potentially affecting their structure, function, and ability to interact with other molecules (Hoffman et al. 2015). The ability of FA to covalently cross-link intracellular and extracellular components may play a vital role in the thickening of the vascular basement membrane structure, which may initiate endothelial cell damage. Moreover, Yu proposed that FA can also increase oxidative stress, in turn exacerbating advanced glycation, which is well known to play an important role in diabetes complications (Yu 1998). The endothelial dysfunction associated with diabetes is a critical pathophysiological step in the early stage of vascular diabetic complications, which contributes to the development of organ damage, such as in the brain, retina, heart, and kidneys, in diabetes patients (Hadi et al. 2007). In addition, a robust activatable two-photon fluorescent probe to visualize endogenous formaldehyde as a biomarker for diagnosis and evaluation of DM (Wang et al. 2023).

3 FA and Atherosclerosis

Diabetes patients are at risk of atherosclerosis, one of the most well-known diabetic macrovascular complications (Um et al. 2016). The risk factors associated with atherosclerosis include chronic progressive vascular endothelial injuries and inflammatory factors (Su et al. 2017). SSAO activity in the serum is increased in DM, and it has also been implicated in atherosclerosis (Mészáros et al. 1999). Yu et al. found that methylamine has strong toxic effects on the endothelium of the human umbilical vein and bovine pulmonary artery in the presence of SSAO enzymes (Yu et al. 1993), suggesting that SSAO-mediated production of FA is involved in the toxic effect of methylamine.

On the one hand, FA is highly reactive and is considered a potent inflammatory agent. FA can lead to protein–protein cross-links and DNA–protein cross-links, suggesting that SSAO-mediated FA interacts with membrane proteins in the vessel wall to form irreversible cross-linked complexes, which initiate endothelial injury (Gubisne-Haberle et al. 2004). As described by Yu et al. (1998), FA production mediated by SSAO plays a role in amyloid and vascular plaque formation. Furthermore, FA was found to have an apparent toxic effect on rat aortic A7r5 cells, resulting in cell apoptosis when the concentration of FA reached 0.5 mM. The mechanism may be that FA interacts with proteins, DNA, and other macromolecular substances to form cross-links, causing a change in mitochondrial membrane structure, which leads to the opening of mitochondrial membrane pores, the release of cytochrome C into the cytosol, and caspase activation. It may eventually damage vascular wall cells and participate in the formation of atherosclerosis (Hernandez et al. 2006). On the other hand, the deamination of methylamine catalyzed by SSAO produces not only FA but also hydrogen peroxide (H₂O₂). H₂O2, as a significant reactive oxygen species, is the principal generator of oxidative stress (Tyihák et al. 2001). Under alkaline conditions, the reaction of H₂O₂ with FA can also produce free radicals, producing the oxidation of low-density lipoprotein and protein glycation (Yu et al. 2003). Therefore, the production of SSAO-mediated FA and H₂O₂ has been considered a potential risk factor for stress-related angiopathy.

Additionally, cigarette smoke contains large amounts of reactive aldehydes such as FA and acetaldehyde. These molecules may inactivate lecithin cholesterol acyltransferase through their reaction with active cysteine radicals, weakening cholesterol-mediated reverse transport by high-density lipoprotein and eventually promoting atherosclerosis formation (Chen et al. 1995).

4 FA and Diabetic Retinopathy

Most patients suffer from some degree of retinopathy in the late stage of DM (Wong et al. 2016). Diabetic retinopathy is caused by complex pathophysiological mechanisms triggered by hyperglycemia. Several mechanisms are involved in diabetic retinopathy, including hypoxia, tight junction abnormalities, inflammatory factors, and capillary basement membrane thickening (Roy et al. 2011; Coughlin et al. 2017; You et al. 2019).

We hypothesized that FA might be closely related to the occurrence and development of diabetic retinopathy for the following reasons. (1) Clinical studies have shown that the activity of SSAO in patients with diabetes is significantly increased, resulting in an increase in cytotoxic products (especially FA). SSAO is selectively distributed in vascular smooth muscle, retina, kidney, and blood circulation, which are often destroyed in DM patients (Garpenstrand et al. 1999). Thus, the metabolic formation and accumulation of FAs are likely to increase in the retinas of DM patients. (2) Methanol is harmful to human optic nerves and retinas, and the metabolic products of methanol, such as FA and formic acid, contribute to the formation of ocular tissue toxicity (Liberski et al. 2022). An experiment on the rabbit model showed mild posterior subcapsular cataract and retinal lesions in fundoscopy after the injection of 0.1 and 1.0% FA for 30 days. Histologically disorganized retinas and optic nerves were also found in rabbit eyes (Hayasaka et al. 2001). These data indicate that the toxic effect of FA on the retina should not be ignored. (3) In DM patients, FA may contribute to the thickening of the capillary basement membrane. Proteins in the capillary basement membrane can be cross-linked by FA, leading to an increase in their synthesis, such as collagen IV, fibronectin, and laminin (Zhu 2022). Such matrix modifications might inhibit endothelial-pericyte communication, alter their interaction with basement membrane proteins, and lead to the development of retinopathy. (4) The retina is one of the highest energy-demanding organs and requires a continuous supply of oxygen and energy (Urs et al. 2018). FA may cause extensive cross-links between mitochondrial and cellular proteins, resulting in mitochondrial damage (Persson et al. 2012). In addition, FA dehydrogenase can convert formic acid, which can induce mitochondrial superoxide accumulation, leading to mitochondrial injury and oxidative cell death (Bralet et al. 1991). These mechanisms ultimately lead to mitochondrial respiratory depression, resulting in a state of retinal hypoxia that aggravates the severity of retinopathy in DM patients.

5 FA and Diabetic Nephropathy

The kidney is one of the main organs affected by microvascular injury in advanced DM patients, and diabetic nephropathy is one of the most severe complications in patients with DM (Coughlan et al. 2007). However, the susceptibility factors and pathogenesis of diabetic nephropathy are not clear. Hyperglycemia commonly affects specific cellular changes in the kidneys, including endothelial cells, renal tubular epithelial cells, renal interstitial fibroblasts, podocytes, and mesangial cells, which contribute to the pathogenesis of diabetic nephropathy (Yang et al. 2021).

Podocytes and epithelial cells, together with the glomerular basal membrane (GBM), form the glomerular filtration barrier of the kidney (Faul et al. 2007). The thickening of the GBM is one of the defining characteristics of diabetic nephropathy (Phillips et al. 2011). Zhu et al. (2022) proposed possible pathways of FA/formic acid-mediated diabetic kidney damage as follows. First, the effect of FA on cross-linking proteins contributes to GBM thickening and GBM charge changes, reducing the dilatation of the capillary wall and promoting glomerular injury, which contributes to the generation of proteinuria in DM patients. In addition, FA/formic acid can induce hypoxic injury in glomerular mesangial cells, resulting in focal mesangial lysis. This leads to the overgrowth of mesangial cells and an increase in extracellular matrix production, which results in the expansion of mesangial tissue. Last, due to chronic renal hypoxia and adenosine triphosphate (ATP) deficiency caused by FA/formic acid, some compensatory changes to the kidney occur, but eventually, these changes become harmful. In summary, the formation and accumulation of FA and formic acid in DM patients may be one of the crucial determinants of diabetic nephropathy.

6 FA and Cognitive Impairment

Endogenous FA is involved in memory performance and closely related to some severe diseases, such as AD, DM, and depression (Tong et al. 2008). People with diabetes often suffer from cognitive impairments due to the devastating effects of diabetes, and growing evidence supports a close link between AD-related dementia and DM (Ryan et al. 2006; Koekkoek et al. 2015).

Recently, many researchers have evaluated the neurotoxic effects of chronic FA exposure. Different AD animal models, such as senescence-accelerated prone mice, APP-transgenic mice, and APP/PS1-transgenic mice, showed pathological levels of FA in the hippocampi (Tong et al. 2011). Zhai et al. demonstrated that FA induced AD-like pathologies and cognitive deficits in rhesus monkeys (Zhai et al. 2018). Many studies have reported that increased FA could lead to amyloid-beta (Aβ) protein aggregation, Tau protein aggregation, and hyperphosphorylation in vitro and in vivo, which are confirmed biomarkers for AD (Chen et al. 2007; Lu et al. 2013; Rizak et al. 2014). According to Yu, FA can exacerbate advanced glycation and thus increase protein cross-linking complexity (Yu 1998). It has been confirmed that abnormal accumulation of advanced glycation end-products (AGEs) plays a nonnegligible role in Aβ-mediated neurotoxicity. In addition, the AGE-RAGE pathway can induce phosphorylation of Tau protein, which ultimately leads to impairment of spatial memory ability in diabetes (Li et al. 2012). This could imply that FA is involved in the pathogenesis of cognitive impairment in diabetic patients by accelerating the glycation process.

Moreover, clinical studies have reported increased levels of FA in patients with AD, which was negatively correlated with Mini-Mental Status Exam (MMSE) scores (Tong et al. 2011). Consistent with this study, Arvanitakis et al. found that patients with T2D diabetes had significantly lower MMSE scores than healthy controls, and the memory and cognitive abilities of diabetic patients were also impaired (Arvanitakis et al. 2004). Subsequently, Tan et al. suggested that FA could induce hyperglycemia and cognitive impairment. Transgenic overexpression of human mitochondrial aldehyde dehydrogenase 2 (ALDH2) can reduce both FA and blood glucose levels, thereby reducing cognitive impairment in diabetic model mice (Tan et al. 2018). ALDH2 plays a significant role in lowering the concentrations of FA in the presence of glutathione depletion in DM, which may be one of the mechanisms of elevated FA in diabetic patients (Dicker et al. 1986). Meanwhile, Tong et al. suggested that measuring FA in overnight fasting urine could be a potential method for evaluating cognitive impairment in dementia. Additionally, this study revealed an increase in urine FA caused by overexpression of SSAO in the blood (Tong et al. 2017). As mentioned above, serum SSAO activity is elevated in diabetic patients and associated with FA accumulation. This partly explains why people with diabetes are more likely to develop AD.

7 Determination and Clearance of Endogenous FA in Diabetes

Since FA plays an important role in the progression of diabetic complications, much attention has recently been paid to the development of methods to assay endogenous FA. One of the most exciting advances in this area is the development of fluorescent probes of dicarbonyl compounds (Huang et al. 2022). Tang et al. prepared robust fluorescent probes for tracking endogenous FA in living cells and mouse tissue slices (Tang et al. 2020). In particular, probes for dicarbonyls such as monocarbonyls include FA, carbon monoxide (CO), and phosgene along with methylglyoxal (MGO) and malondialdehyde (MDA) (Jana et al. 2022). These reactive carbonyl adducts are believed to be involved in diabetic complications. Moreover, some studies have detected elevated levels of methanol and FA in the exhaled breath of patients with advanced diabetes (Zhu 2022). Interestingly, as described, metformin attenuated FA-induced fluorescence in BSA as well as the aggregation of γH2AX in HepG2 cells. Thus, metformin can protect against protein and DNA damage induced by FA at least partly through a direct reaction process (Mai et al. 2020). More FA scavengers will be introduced in Chap. 18.

8 Conclusion and Prospects

A novel hypothesis regarding clinical complications associated with diabetes has been proposed in this review. The role of FA, especially endogenous FA, in diabetes and its complications has begun to receive attention. Endogenous FAs can interact with nucleic acids and proteins to form irreversible cross-linking complexes, which affect the structure and function of biomacromolecules, leading to extensive vascular disease and impairing the function of organs such as the retina, kidneys, and brain. These then participate in the occurrence and development of diabetes. Continuing to study the unique role of FA in diabetes and its complications, including cognitive impairment, is essential to improve our understanding of DM and may potentially provide new prevention or treatment strategies.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_15

15. Formaldehyde Affects Lifespan and Stress Resistance in Drosophila

Yining Li¹ and Rongqiao He2  

(1)

Chinese Institute for Brain Research, Beijing, China

(2)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Longevity is a fundamental and fascinating topic in contemporary biological studies. Many genes, signaling pathways, and transcription factors have been reported to affect lifespan from yeast to humans. Formaldehyde participates in epigenetic regulatory roles in the methylation and demethylation of DNA, RNA, and histones and exerts various toxic effects from animals to humans at higher concentrations, while the effects of lower concentrations have rarely been reported. We used Drosophila as a model organism to study the effects of formaldehyde at various concentrations on longevity and found that different concentrations of formaldehyde played different roles in lifespan and stress resistance in Drosophila. Since knocking down the expression level of formaldehyde dehydrogenase (FDH) in the neural system of Drosophila could also extend lifespan and increase stress resistance, it is a hopeful way to screen for the genes in the Drosophila neural system to study the probable molecular mechanisms of longevity. In this chapter, we reviewed the progress of lifespan studies in Drosophila and their relationship with formaldehyde, de/methylation and FDH and proposed the hypothesis that balanced levels of formaldehyde in epigenetics and FDH improve lifespan. Formaldehyde is involved in epigenetics through its participation in methylation and demethylation, including its relationship with FDH, thereby improving lifespan within a narrow range of concentrations.

Keywords

FormaldehydeLifespanStress resistanceDrosophilaEpigenetics

Abbreviations

A

ADH

Alcohol dehydrogenase

ADH III

Type III alcohol dehydrogenase

C

cGMP

Cyclic 3′,5′-guanosine monophosphate

CR

Caloric restriction

D

DNA

Deoxyribonucleic acid

DR

Dietary restriction

F

FDH

Formaldehyde dehydrogenase

G

GHNHOH

S-(hydroxysulfenamide)glutathione

GSH

Glutathione

GSNO

S-Nitrosoglutathione

GSNOR

S-Nitrosoglutathione reductase

GSSG

Glutathione disulfide

H

HPLC

High-performance liquid chromatography

I

ICR

Institute of Cancer Research

IGF-1

Insulin-like growth factor 1

K

KI

Knock-in

KO

Knock-out

M

MDR

Medium-chain dehydrogenase/reductase

mM

Millimolar

N

NADH

Nicotinamide adenine dinucleotide

NO

Nitric oxide

O

OR83b

Olfactory receptor 83b

R

RNA

Ribonucleic acid

1 Introduction

All multicellular organisms, such as mammals, undergo many physiological, morphological, cellular, and molecular changes, which lead to death as a final end point (Balcombe and Sinclair 2001). Although aging is still regarded as an unsolved problem, it has already been proven that the aging process can be regulated by many genes, signaling pathways, and transcription factors in addition to environmental effects (Kenyon 2010). Since short-lived animals might die of novel diseases that are unrelated to normal aging, it is a more hopeful way to search for mutants and factors that could prolong lifespan to study aging mechanisms (Rose et al. 1992). Many methods have been reported to increase lifespan, including physical stimuli, chemical molecule usage, and genetic mutations (Kenyon 2010).

As described previously (the Environmental Protection Agency, USA “Toxicological Review of Formaldehyde Inhalation Assessment” June 18, 2010), all living organisms produce and process formaldehyde (Su et al. 2016). Formaldehyde plays a role in the methylation and demethylation of DNA (Yan and Fujimori 2011; Crider et al. 2012), histones (Li et al. 2014; Shi et al. 2004), and RNA (Gerken et al. 2007; Su et al. 2015), suggesting that this compound is involved in gene regulation, particularly epigenetic events. Furthermore, levels of endogenous formaldehyde increase with human aging older than 75 years (Tong et al. 2013b). The best-known phenomenon exemplifying epigenetic drift (the alteration of epigenetic patterns during aging) is the gradual decrease in global DNA methylation (Sierra et al. 2015). DNA methylation appears to be a dynamic tool of transcriptional regulation, with an extra level of complexity due to the recent discovery of the conversion of 5-methylcytosine into 5-hydroxymethylcytosine. This age-related DNA demethylation is associated with changes in histone modification patterns. Demethylation produces formaldehyde (Lardenoije et al. 2015). Thus, we considered that endogenous formaldehyde might be involved in lifespan since it plays a role in epigenetic events (Tong et al. 2011). Here, we observed that different concentrations of formaldehyde could exert different effects on Drosophila lifespan. A lower concentration of formaldehyde could prolong the lifespan, while a higher concentration could decrease the lifespan. In this chapter, we discuss the relationship between formaldehyde and lifespan studies in Drosophila.

2 Formaldehyde and Lifespan

Many studies have reported the toxic effects of formaldehyde on animals and humans (Kilburn et al. 1987; Qiang et al. 2014). However, differences in the effects on longevity among various concentrations of formaldehyde have rarely been reported.

As described previously by Su et al., the porcine brain contains 75.5–83.4 μmol/kg formaldehyde in fresh brain tissues measured by high-performance liquid chromatography (HPLC) coupled with 2,4-dinitrophenylhydrazone (Su et al. 2011). Yang and coworkers fed 2-month-old Institute of Cancer Research (ICR) mice with 2 and 3.8% methanol in water (formaldehyde as its metabolite) for 6 months, which resulted in cognitive impairment and Tau hyperphosphorylation in their brain (Yang et al. 2014a). The concentrations of blood formaldehyde markedly increased during the administration of methanol within water. Administration of 3% methanol could induce amyloid β deposition, Tau hyperphosphorylation, neuron death, and cognitive impairment (Yang et al. 2014b). Thus far, it is difficult to feed mammals formaldehyde because the animals refuse to drink aldehydes with irritated odors and tastes.

It calls for a long period to study longevity with mice and other higher animals. The fruit fly Drosophila melanogaster is a powerful genetic model to study aging because of its short life cycle, ease of culture and handling, simple genome, convenient genetic manipulation, and high homology with higher animals (Tower 2011). To systematically study the roles of formaldehyde on longevity, we chose Drosophila as an experimental model and added different amounts of formaldehyde solution into the fly food to make up ten kinds of culture medium with different concentrations of formaldehyde as follows: 0, 0.011, 0.019, 0.026, 0.037, 0.074, 0.111, 0.185, 0.259, and 0.370%. Afterward, nearly 100 single-gender flies were placed into each culture bottle, among which the live flies were counted every 2 or 3 days and transferred into new bottles every week until the last fly died.

The average lifespan of each group of female flies under different concentrations of formaldehyde is shown in Fig. 15.1. The statistical results indicated that different concentrations of formaldehyde played different roles in the lifespan of flies, especially in females. About 0.037% formaldehyde could significantly extend the lifespan of female flies to the highest level, whereas higher concentrations of formaldehyde (≥0.185%) could significantly reduce the lifespan in both male and female flies (Li and He 2016). These results provide a new aspect to study the molecular mechanisms of longevity with the model of Drosophila melanogaster.

Fig. 15.1

Average lifespan of female Drosophila fed by different concentrations of formaldehyde. Compared to the 0% group, female flies fed by 0.026%, 0.037%, and 0.074% formaldehyde in food significantly increased lifespan, whereas 0.185% and higher concentrations significantly decreased lifespan (n = 100 for each group, *p < 0.05, ***p < 0.001) (Li and He 2016)

3 Genes and Lifespan

Many genes have been reported to be involved in regulating lifespan. The earliest genes to be found were age-1 and daf-2 in Caenorhabditis elegans (Friedman and Johnson 1987; Kenyon et al. 1993). Age-1 mutants reduce the propagating fecundity of worms to prolong lifespan, while daf-2 participates in the insulin/insulin-like growth factor 1 (IGF-1) pathway to regulate metabolism and then affect lifespan. This pathway is highly conserved in evolution. Mutants of the insulin/IGF-1 receptor in Drosophila could also extend lifespan (Tatar et al. 2001). In C. elegans, this pathway also calls for the participation of daf-16. In Drosophila, the most similar gene is dFOXO (Hwangbo et al. 2004). In mice, insulin and IGF-1 work through different receptors, and both receptors can extend lifespan at different levels (Blüher et al. 2003; Holzenberger et al. 2003).

We are interested in the gene of formaldehyde dehydrogenase (FDH), which is one of the most ancient members of alcohol dehydrogenases (ADH) and belongs to the gene family of medium-chain dehydrogenase/reductase (MDR) (Persson et al. 2008). FDH persists in organisms from prokaryotes to humans, and it is highly conserved among these species (Danielsson and Jörnvall 1992).

FDH was first separated from other types of ADH by a rapid microelectrophoretic technique in Drosophila (Ursprung and Leone 1965) and was localized to the third chromosome, which is different from ADH (Courtright et al. 1966). In addition to its catalytic activity on formaldehyde, FDH can also catalyze octanol efficiently (Sieber et al. 1972; Danielsson et al. 1994).

In mammals, type III alcohol dehydrogenase (ADH III) is also called S-nitrosoglutathione reductase (GSNOR), which catalyzes the reduction reaction of S-nitrosoglutathione (GSNO) (Jensen et al. 1998). Since GSNO is a key protein in the metabolic pathway of NO, ADH III participates in the metabolism of NO through the degradation of GSNO.

Drosophila FDH is most similar to GSNOR. Overexpression of FDH in Drosophila fan-shaped body could decrease the visual learning ability of the flies, and this phenotype could be rescued by overexpression of cyclic 3′,5′-guanosine monophosphate (cGMP), which is necessary for the function of learning and memory (Hou et al. 2011). Pecsenye et al. restricted the sugar input of Drosophila and found that the catalytic activity of FDH increased in fly larvae but reduced in adult flies (Pecsenye et al. 1994). This phenomenon could also be affected by temperature. In larvae, the increasing level was more significant at 18 °C than at 26 °C (Pecsenye et al. 1996). Antosh et al. performed a screen in flies and mice whose lifespans were increased by food restriction and by adding resveratrol, respectively. Fdh was found to be upregulated in flies and Adh5 (a homolog of Drosophila fdh) was upregulated in mice by both methods (Antosh et al. 2011). This result indicated that FDH might be closely related to longevity in both insects and mammals.

To study the roles of the fdh gene more clearly, we knocked down the expression level of the fdh gene in the Drosophila neural system by RNAi. The preliminary results showed that the lifespan was significantly extended under both laboratory culture conditions and starvation conditions (Li and He, unpublished data). Investigating the relationship among the fdh gene, formaldehyde, and lifespan will provide a new way to elucidate the mechanism of longevity.

4 Formaldehyde and Stress Resistance

Mutants with a lengthened lifespan are always accompanied by strengthened stress resistance, which includes starvation, heat shock, and reactive oxygen species (ROS) stress (Martin et al. 1996). Some long-lived mutants increase their resistance to only one type of stress, while other mutants can resist two or more kinds of stresses simultaneously (Wang et al. 2004). The age-1 and daf-2 mutants in worms could resist reactive oxygen species, ultraviolet radiation, and heat shock. Meanwhile, mth and EcR mutants in flies exhibited increased resistance to paraquat, starvation, and heat shock (Lin et al. 1998; Simon et al. 2003). A study in 2004 screened for the genes that were upregulated or downregulated by three of these stresses and finally found 13 genes responding to all of them (Wang et al. 2004).

We further tested the effect of 0.037% formaldehyde on stress resistance, including starvation, heat shock, and paraquat, and found that 0.037% formaldehyde significantly increased starvation resistance and heat shock resistance but reduced oxidative resistance in both male and female flies. Figure 15.2 shows the results in female flies as an example.

Fig. 15.2

Survival time under different stresses of female Drosophila fed by 0.037% formaldehyde. Compared to the 0% group, female flies fed by 0.037% formaldehyde in food significantly increased starvation resistance and heat shock resistance, but reduced oxidative resistance (n = 75–100 for each group, ***p < 0.001) (Li and He 2016)

5 Hormesis and Lifespan

The earliest way to prolong lifespan is hormesis, in which mild exposure to an originally lethal stress factor becomes beneficial in many organisms (Sørensen et al. 2007). The most common approach of hormesis include radiation, heat shock stress, food limitation, oxidative stress, and so on (Rattan 2008). The most traditional way to prolong lifespan is dietary restriction (DR). Since food provides most of the calories in animals, restricting food input is to restrict the calorie input. Therefore, DR is also called caloric restriction (CR). DR was found in rodents in the 1930s, and later, its existence was also proven in yeast, worms, flies, and humans (Kenyon 2011; Rogina and Helfand 2004).

Since formaldehyde is harmful and even lethal at higher concentrations but becomes beneficial at lower concentrations, we have regarded the effect of formaldehyde on lifespan as a kind of hormesis, which might activate the homeodynamic pathways of maintenance and repair and then lead to beneficial hormetic effects (Rattan 2008). As described by Kumar et al. (2012), oxidization of formaldehyde results in Nicotinamide adenine dinucleotide (NADH) generation, which contributes to reduction in ROS and increased adenosine triphosphate (ATP) generation levels under carbon starvation conditions, which might be one of the mechanisms that bring about the positive effects of Hormesis. Application of the hormesis effect of formaldehyde would develop a new aspect of research and therapy for the aging problem.

6 Neural System and Lifespan

There are many factors and molecules in the neural system that play great roles in the lifespan of animals. In Drosophila, the prolonging effect of DR is mainly due to the yeast in the food (Mair et al. 2005). If the DR flies are allowed to smell the odor of yeast, then the lifespan elevation effect of DR is dismissed. Mutating the olfactory receptor OR83b could also prolong lifespan. These results suggested that the olfactory system could play an important role in the regulation of lifespan (Libert et al. 2007).

Social relationships also play important roles in lifespan. The lifespan of male Drosophila is reduced after copulation with females, and this phenomenon is regarded as a cost of reproduction. In addition, contact without copulation of males and females could also reduce lifespan. This is intermediated by a gustatory receptor named ppk23 (Gendron et al. 2014).

In addition to sensory systems such as olfactory and gustatory organs, there are many other molecules regulating lifespan and stress resistance in the neural system. The most famous longevity pathway of insulin works in the neurons of C. elegans but not in muscle or intestine (Wolkow et al. 2000). Overexpression of the Sir2 gene in the neural system could extend lifespan by regulating the DR effect. Overexpression of the human SOD1 gene in the motor neurons of Drosophila could also prolong the lifespan (Parkes et al. 1998).

7 Low Concentrations of Formaldehyde Enhance Cell Proliferation

As shown in Fig. 15.1, formaldehyde has an optimal concentration to prolong Drosophila lifespan, but either higher or lower concentrations lead to a decrease in the effect. The same phenomena have also been observed in cell culture in the presence of formaldehyde. Decreasing the dose of formaldehyde in the culture medium could improve cell proliferation in many cell lines. The proliferation of HeLa cells and human malignant melanoma SK-MEL-28 cells was promoted in the presence of 10 μM formaldehyde (Ke et al. 2014; Rizzi et al. 2016). Low concentrations of formaldehyde (10–25 μM) stimulate proliferation in both human low-invasive A375P and high-invasive SK-MEL-28 cells (Rizzi et al. 2014, 2016). As described by Tyihak et al., the proper concentration of formaldehyde not only enhances proliferation but also reduces apoptosis in human colon carcinoma HT-29 cells and human endothelial HUV-EC-C cells (Tyihak et al. 2001). They first found that formaldehyde (0.1 mM) could decrease the apoptotic activity of cultured cells. Similar results were also observed by using SH-SY5Y cells and BV2 cells from the neural system in our laboratory (Li et al. 2021). Moreover, the addition of glutathione (GSH) to SH-SY5Y cells treated with formaldehyde did not show a significant rescuing effect on their viability compared to the control (Miao et al. 2013). Since GSH is an important component of the nitrosylation pathway, the results indicated that formaldehyde works in an independent manner from nitrosylation. It would be helpful to test whether formaldehyde could improve the growth of more neural cell lines from various regions. The probable mechanisms of proliferation enhancement and lifespan improvement in the presence of formaldehyde need to be further clarified.

8 Possible Mechanisms by Which Formaldehyde Prolongs Lifespan

The mechanisms by which supplementary formaldehyde expands the flies’ lifespan still need to be illustrated. Lifespan may benefit from the balance in the metabolism of formaldehyde, which is a multiple functional compound in organisms. Among them, it is worth discussing GSNOR, which is involved in the pathways of not only formaldehyde but also nitrosylation (Mattapally and Banerjee 2011) and retinoic acid (Galbis-Estrada et al. 2012).

As described by Speit et al. (2010), the human lung cell line A549 exposed to formaldehyde (50–300 μM, 1, 4, or 24 h) did not reveal altered expression of ADH3. Several studies exhibited similar results in that the expression level of GSNOR is not regulated by formaldehyde exposure (Neuss et al. 2010; Zeller et al. 2011). The unchanged expression of GSNOR suggests that prolonging the lifespan of flies with formaldehyde ingested in food may activate other metabolic pathways, except for the nitric oxide (NO) pathway.

There are still some conflicting results on mammalian GSNOR levels and aging. A series of studies have shown that loss of function in GSNOR brings about a number of negative effects. GSNOR-KO mice exhibited dysregulation of blood pressure and increased mortality induced by endotoxic shock (Liu et al. 2004). In the immune system, GSNOR-deficient mice induced apoptosis of lymphocytes in the thymus and widespread lymphopenia (Yang et al. 2010). In hepatocytes, GSNOR deficiency caused cytotoxic DNA damage, inhibited DNA repair, and increased hepatocellular carcinoma (Wei et al. 2010, 2011). In young GSNOR-KO mice, muscle fiber size and nerve axon number were reduced, and these neuromuscular changes mimicked senescence phenotypes (Montagna et al. 2014). Mitochondria are also impaired, depolarized, and highly fragmented in GSNOR deficiency (Rizza et al. 2018; Rizza and Filomeni 2018), while GSNOR expression and activity are reduced in primary senescent cells that accumulate during aging in rodents and humans (Rizza et al. 2018).

However, some other authors observed that GSNOR increased dramatically with age in both the mouse and human hippocampus and knocking out of GSNOR rescued age-related cognitive impairments (Zhang et al. 2017). GSNOR-KO mice exhibited improved survival and cardiac performance after myocardial infarction (Hatzistergos et al. 2015), reduced myocardial infarct size, and preserved ventricular systolic and diastolic function after left coronary artery ligation (Lima et al. 2009).

To understand the paradoxical results, it was considered that GSNOR might play positive roles in health only when its expression level remained in a certain range. This leads to the Goldilocks principle (Larrick and Mendelsohn 2019), which means that its levels need to be maintained in a narrow range when it is involved in aging. This viewpoint is consistent with our observations. First, we observed the improvement in Drosophila longevity when feeding on a certain amount of formaldehyde in their food (Li and He 2016). Either more or less formaldehyde does not benefit. Second, incubation of neural cells with different concentrations of formaldehyde for 3 days resulted in an increase in cell proliferation when the aldehyde was administered at lower concentrations (0.01–0.05 mM for SH-SY5Y cells; 0.001–0.05 mM for BV2 cells), whereas treatment with higher formaldehyde concentrations (>0.05 mM) led to increased cell death (Li et al. 2021). Third, in accordance with adding a certain amount of formaldehyde to Drosophila food, knocking down GSNOR to a certain level in the fly neural system significantly extended lifespan and starvation resistance (Li and He 2016).

As described by Jopp et al. (2016), the somewhat higher cognitive capacity may be related to the fact that the number of centenarians living in the community was substantially higher in the present study than in other US centenarian studies. Commonsensibly, maintaining normal cognitive abilities is beneficial for older people to live longer since cognitive ability is associated with lifespan (Unno et al. 2011, 2020). Therefore, in addition to longevity, we would like to consider cognitive ability by both GSNOR and endogenous formaldehyde. There are also a range of observations. First, according to Tong et al. (2013a), either an abnormal excess or a deficiency of endogenous formaldehyde leads to memory impairments in rodents. Second, GSNOR-KI mice showed cognitive impairment, but GSNOR-KO mice rescued age-related cognitive impairment (Zhang et al. 2017). Third, however, intraperitoneal injection of formaldehyde rescued cognitive impairment in GSNOR-KI mice in the Morris water maze, suggesting that formaldehyde plays an important role in cognitive ability in the GSNOR pathway. Fourth, intraperitoneal injection of arginine could also rescue cognitive impairment, while hippocampal NO levels were not markedly changed and were different between GSNOR-KI and wild-type mice (Zhang et al. 2017). Arginine is also converted to glutamate and serotonin, which are the most important neurotransmitters functioning in cognitive abilities (Köhler et al. 2008). Thus, the effect of arginine on cognitive function through the regulation of glutamate or serotonin should not be excluded in addition to the NO effect. Taken together, as a multiple functional molecule, the mechanisms of formaldehyde on cognition and lifespan should not be neglected, and the functional pathways involved in GSNOR in addition to the nitrosylation pathway call for further clarification.

Since formaldehyde acts as a donor for methylation of DNA, RNA, and histones, we consider that formaldehyde-induced extension of lifespan is involved in epigenetics. There is accumulating evidence linking aging to genetic and epigenetic alterations (Sen et al. 2016; Morris et al. 2019). In the aging process, global and local changes in DNA methylation, histone modification, and chromatin remodeling exist in all aging model organisms. Globally knocking down the activating regulators of methylation and overexpressing the repressive regulators could improve lifespan in worms (Han and Brunet, 2012), and these effects are transgenerational (Maures et al. 2011). Similarly, decreasing the global levels of positive marks such as H3K4me3 in flies led to lifespan extension (Li et al. 2010). However, reducing the global levels of repressive regulators H3K27me3 in flies (Siebold et al. 2010) also prolonged lifespan, which seemed to be opposite to worms. In mammals, a recent study used a system that introduced specific DNA breaks and therefore produced inducible changes to the epigenome and found that aging was dramatically accelerated due to the global loss of epigenomic information driven by DNA repair (Yang et al. 2023).

Here, we emphasize that the effect of formaldehyde on lifespan involves an epigenetic mechanism. First, formaldehyde, a one-carbon unit derived from both endogenous sources and environmental exposure, acts globally as a donor for methylation and as a product for the demethylation of DNA, RNA, and histones (Huang et al. 2014; Li et al. 2021). Second, as described by Tong et al. (2013a), enhancing DNA demethylation by a DNA demethylating agent or scavenging elevated formaldehyde by alcohol-degrading enzyme (ADH5) both led to spatial memory deficits by blocking DNA remethylation in rats. This indicates that either more or less endogenous formaldehyde disturbs the learning and memory of mice (Qiang et al. 2014). These findings lead to homeostasis in formaldehyde metabolism; that is, an imbalance in metabolic formaldehyde impairs cellular function and even cell death (Xiao and He 2017). Third, cell senescence, as well as mouse and human aging, is characterized by an epigenetically driven decrease in ADH5/GSNOR, suggesting that ADH5 may act as a new longevity gene (Rizza & Filomeni 2018). Fourth, formaldehyde regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells, affecting methylation and demethylation (Pham et al. 2023). Finally, there is another possible mechanism by which formaldehyde reacts with cysteine, releasing a condensation product (thiazolidine-4-carboxylic acid, a cyclic sulfur amino acid) (Weber et al. 1982). The addition of thiazolidine-4-carboxylic acid to the diet slowed the aging process in mammals and prolonged their lifespan. Taken together, formaldehyde should be maintained at proper levels to improve lifespan in a formaldehyde concentration-dependent manner (Fig. 15.3).

Fig. 15.3

A putative pathway showed the probable relationship among formaldehyde, GSNOR and lifespan. It is a hypothesis that keeping formaldehyde and ADH5/GSNOR levels in a proper range may improve an animal lifespan

9 Perspective

Although many molecules were discovered and reported to affect lifespan, it is still far away to illustrate how they work together and define the lifespan of organisms. Stepping on to search for the key molecules that greatly affect lifespan will firmly promote the study of this area. Since knocking down the expression level of the fdh gene in the Drosophila neural system could prolong lifespan and increase stress resistance, it would be valuable to perform a screen in the Drosophila neural system to investigate the probable neuronal mechanisms and pathways of formaldehyde and the fdh gene in aging. Since epigenetics is closely related to the regulation of aging and lifespan, the possibility of formaldehyde extending lifespan through its function in the methylation and demethylation of DNA, RNA, and histones should also be emphasized and detected further.

Stress resistance is a convenient experimental method since it has a much shorter period than the natural lifespan. Using the knockout mutants in the Drosophila neurotransmitter system, the flies could be fed with 0.037% formaldehyde in food and screened under starvation or heat shock conditions, searching for the mutants whose lifespan-increasing phenotype by 0.037% formaldehyde is reduced to the same level as wild type or elevated to an even higher level. Then, the lifespan changes of these mutants under normal culturing conditions with or without formaldehyde will be observed, and the mechanisms of formaldehyde on lifespan will be investigated. This research might cast new light on the aging problem and help us approach the dream of prolonging lifespan and deferring senescence in the future, which might not be quite far away.

Acknowledgments

All grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_16

16. Molecular, Cellular, and Animal Experiments in Formaldehyde Study

Xuechao Fei1, 2, BeiBei Wu³, Min Qiang⁴, Zhiqian Tong⁵ and Rongqiao He6  

(1)

Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Peking Union Medical College, Beijing, China

(2)

Institute of Basic Medical Sciences, Neuroscience Center, National Human Brain Bank for Development and Function, Chinese Academy of Medical Sciences, Beijing, China

(3)

Department of Physiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

(4)

Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai, China

(5)

Center for Cognitive Disorders, Beijing Geriatric Hospital, Beijing, China

(6)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Alzheimer’s disease (AD), which involved in many molecular pathways in the human central nervous system, is a multifactorial complex neurodegenerative disease. The failure of the recent development of AD therapeutic agents in clinical trials is mainly due to their single-target or single-pathogenic pathway effect or late time window for treatments. The metabolism of formaldehyde involves multiple pathways and gene regulation. According to recent studies, endogenous formaldehyde levels are positively related to the severity of age-related cognitive impairment, with approximately 40% of AD patients suffering from dysmetabolism of formaldehyde. Furthermore, administration of a low concentration of methanol in monkeys, a precursor compound for formaldehyde, induces cognitive impairment accompanied by Aβ deposition and the formation of senile plaque, tau hyperphosphorylation, and aggregation. This evidence suggests that formaldehyde plays a role in the progression of AD. As shown in clinical investigations, urine formaldehyde, including formic acid, is related to age-related cognitive impairment. Endogenous formaldehyde and formic acid are expected be biomarkers in clinical determination. Development of useful biomarkers will be beneficial to enlighten the understanding of the role of formaldehyde in the neurodegenerative disease, especially age-related cognitive impairment. In this chapter, we review some relevent protocols, experimental models (including molecular, cellular and animal models) and clinical investigations pertaining to formaldehyde research, drawing from our own work and contributions by colleags in the field.

Keywords

FormaldehydeCompoundsCell cultureAnimal modelsIntraperitoneal injectionIntracerebroventricular injection

Abbreviations

A

AD

Alzheimer’s disease

ADH3

Alcohol dehydrogenase III

ALDH

Aldehyde dehydrogenase

AGES

Advanced glycation end-products

D

DNMT

DNA methyltransferase

DNPH

2, 4-dinitrophenylhydrazine

F

FA

Formaldehyde

G

GSNOR

S-nitrosoglutathione reductase

H

HFS

High-frequency stimulation

HPLC

High-performance liquid chromatography

5-HT

5-Hydroxytryptamine

L

LTP

Long-term potentiation

M

MCI

Mild cognitive impairment

MMSE

Mini-Mental Status Examination

MoCA

Montreal Cognitive Assessment

MWM

Morris water maze

N

N2a

Neuro-2a cells

NC

Normal controls

NO

Nitric oxide

S

SAMP

Senescence-prone strains

SAMR

Senescence-resistant strains

SAM

Senescence-accelerated mouse

SD

Sprague-Dawley

SCD

Subjective cognitive decline

Obj-SCD

Objectively defined subtle cognitive decline

SSAO

Semicarbazide-sensitive amine oxidase

T

T2DM

Type 2 diabetes mellitus

1 Introduction

Many models have been used to study the effects of formaldehyde (FA) on molecules, cells, and organisms, as well as the related mechanisms. This chapter will introduce commonly used FA-related molecular, cellular, and animal models which are commonly used in recent years. We show the production of FA from the reaction of biochemical compounds such as oxidation of lipids (Li et al. 2008) and sugar decomposition (Wang et al. 2019). Endogenous FA concentrations increase with aging in animals. We injected rodents with FA or administrated methanol to rodents and primates, including Rhesus monkeys, to establish FA-induced models with cognitive impairment. Mice with high concentrations of FA were induced by limited water intake. Transgenic rodents and Drosophila are also introduced. These animal models are valuable for investigating the relationship between FA and cognitive impairment. The animal experiments and the animal models, which were established in the authors’ laboratory, were performed in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals and were approved by the Biological Research Ethics Committee, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

According to numerous studies (Su et al. 2016; Kou et al. 2022), FA accumulation may be one of the key causes of memory impairment in the brain, especially in the hippocampus of animals. FA is involved in triggering abnormal phosphorylation of tau protein and promoting Aβ deposits. Excessive brain FA resulting from either exogenous or endogenous pathways, can induce memory impairment and cognitive decline in different kinds of animal models, including aging animals, transgenic mice, FA- and methanol-administrated animals.

2 Preparation of Formaldehyde with Chemical Compounds

2.1 Oxidation of Myelin Yielding Formaldehyde

Lipid oxidation plays a role in the progression of Alzheimer’s disease (AD) (Ward et al. 2014; Giudetti et al. 2016). Oxidation of lipids for instance myelin oxidation produces aldehydes, including FA (Li et al. 2008). The experiment was performed as follows: N-Acyl-4-sphingosine-1-phosphocholine (1 mg/mL) was incubated with 1 mM H₂O₂ in 50 mM phosphate buffer (pH 7.2) at 37 °C for 24 h to induce lipid oxidation. The level of resultant FA in the reaction mixture was analyzed with high-performance liquid chromatography (HPLC) coupled with 2,4-dinitrophenylhydrazine (DNPH) as described (Su et al. 2011).

2.2 D-Ribose Decomposition Producing Formaldehyde

D-ribose, present in all living cells, is derived from food that contains high amounts of riboflavin and nucleic acids, such as eggs, meat, sea food, and beer. Recent studies suggest that type 2 diabetes mellitus (T2DM) involves dysregulation not only in D-glucose metabolism but also in D-ribose metabolism (Su et al. 2013; Chen et al. 2016). In mice, administration of D-ribose via intraperitoneal injection (once daily for at least 1 month) or gavage (once daily for 6 months) leads to impaired learning and memory ability, accompanied by glia activation, amyloid β (Aβ) deposition, and tau hyperphosphorylation (Han et al. 2014; Wei et al. 2015; Wu et al. 2015).

All reaction mixtures were filtered with 0.22 μM membranes (Millipore, USA) before incubation at 37 °C for different durations. D-Ribose was purchased from Amresco, USA. Other standard reagents and amino acid were obtained from Sigma-Aldrich, USA. Wang et al. incubated D-ribose (final concentration: 100 mM in 20 mM Tris-HCl buffer, pH 8.0, 37 °C, 3 days) and took aliquots for measurements of the concentration FA with 1.0 g/L DNPH (60 °C, 30 min) (Wang et al. 2019). As indicated, D-ribose can partially produce FA in the presence of amino acids (pH = 7.4).

2.3 Formaldehyde from Protein Reacted with Malondialdehyde

Malondialdehyde (MDA) is an active modifying agent of proteins both in vitro and in vivo (Foettinger et al. 2006; Weismann et al. 2011), promoting protein aggregation and amyloid deposition (Allen et al. 1984). MDA-protein aggregates can be continuously internalized by cells, especially under conditions of oxidative stress, which can be induced in various pathological conditions, including cardiovascular and neurodegenerative diseases.

Bovine serum albumin (0.05 mM) was incubated with malondialdehyde (10 mM) in 10 mM phosphate buffer (pH 7.2, 37 °C) for 24 h Then DNPH was added to the reaction mixture as described previously. Aliquots were taken and analyzed by HPLC and a gas chromatography-mass spectrometry (GC-MS; HP6890 GC, USA) for FA quantification (Su et al. 2011). A FA control (33 μM) was included in parallel experiments.

2.4 Formaldehyde Resulted from O-Demethylation Catalyzed by Dioxygenase

As described by Farrow and Facchini (2013), the FA yield increases with the amount of codeine O-demethylase in the assay, where codeine undergoes O-demethylation. Similarly, FA production rises with increasing protopine O-dealkylase levels in cryptopine-containing assays.

2.5 Formaldehyde from Oxidative Demethylation at Serine

Oxidative demethylation at serine8/26 linked with the lysine28 residue in the β-turn of Aβ monomer induces FA generation and FA cross-linking to form Aβ dimers, and then accelerates Aβ oligomerization and fibrillogenesis in vitro. However, Aβ42 mutation in serine8/26, lysine²⁸ abolished Aβ self-aggregation (Fei and Tong 2020).

3 Production of Formaldehyde in Cell Culture

3.1 Formaldehyde in Daily Cell Culture

Generation of FA results from different metabolic pathways, such as demethylation of DNA, RNA and histone, protein denaturation, lipid oxidation, reduced sugar decomposition, and oxidative stress (see Chap. 2). Of course, every cell produces, processes, and uses FA at each moment. Daily cell culture generates FA and releases it into the medium. Thus, FA concentrations can be measured in the culture medium.

Murine neuroblastoma neuro-2a cells (N2a cell line; China Cell Resource Confederation, Beijing, China) were maintained in DMEM-F12 (Corning, USA) supplemented with 10% (v/v) fetal bovine serum (FBS; PAA Laboratories, Pasching, Austria) as monolayer in petri dishes (Corning, USA), at 37 °C and 5% CO₂ with >95% relative humidity. Aliquots of medium were taken for the measurement of FA concentration. In general, the average concentration of FA in the medium released by the cells is 8–11 μM (Wang et al. 2017).

3.2 Yield of Formaldehyde in the Culture of MRMT-1 Cells In Vitro

FA concentration in cultured Matsumoto Rat Mammary Tumor-1 (MRMT-1) cells increased significantly with time from 24 to 72 h. Concentrations of FA increased markedly in tumors of the MRMT-1 subcutaneous vaccination model 7 days after inoculation. Similarly, FA levels rose significantly in the bone marrows and sera of rats with bone cancer pain from day 7 to day 21 (Liu et al. 2013). FA levels were determined by HPLC coupled with fluorescence according to Luo et al. (2001).

3.3 Cells Producing Formaldehyde in the Presence of H₂O₂

Cells (blood endothelial cell line, bEnd.3) were plated (1 × 10⁵ cell/dish) and cultured in DMEM containing 10% fetal calf serum in petri dish (35 mm) in an incubator (37 °C, 5% CO₂) for ≥12 h. The DMEM culture medium was replaced with BBS buffer (136.9 mM NaCl, 5.37 mM KCl, 1.26 mM CaCl₂, 0.81 mM MgSO₄, 0.44 mM KH₂PO₄, 0.335 mM Na₂HPO₄, 10 mM PIPES; pH = 7.2) containing the FA fluorescence probe (FAP-1, final concentration 10 μM) at 37 °C, for 30 min. Following incubation, cells were washed with fresh PBS buffer without the FAP-1 probe. After that, cells were observed under a confocal laser scanning microscope (ZEISS LSM 700 confocal microscope). FAP-1 fluorescence was detected at 688 nm emission with 633 nm excitation. At the same time, MitoTracker Green FM (Cell Signaling, USA) (λex = 490 nm; λem = 516 nm) and LysoTracker Green DND-26 (Cell Signaling, USA) (λex = 504 nm; λem = 511 nm) could be employed for staining of mitochondria and lysosomes, respectively. Lysosomes contribute to the degradation of biomacromolecules and the regulation of channel transporters (Xiong and Zhu 2016). The staining signals showed the location of FA in lysosomes, while mitochondria displayed minimal fluorescence. Afterwards, H₂O₂ was added to bEnd.3 cells when they were cultured in DMEM medium. The signals of FA markedly increased following the addition of H₂O₂ (Chen et al. 2017). In other words, H₂O₂ promotes the cells to produce FA (Fig. 16.1a).

Fig. 16.1

Relation of FA and ROS in bEnd.3 cells detected by flow cytometry. (a) Changes in the fluorescence intensity of formaldehyde probe after addition of ROS to culture medium of bEnd.3 cells; (b) Changes in the fluorescence intensity of ROS probe after addition of FA. The data were obtained at least three independent experiments. All values are expressed as the mean ± s.d.; FA FA. ***p < 0.001. (Chen et al. 2017)

Early-onset AD has been found to be related to an Aβ mutation at glutamic acid 22 to lysine (Italian type E22K) (Miravalle et al. 2000). Jiang et al. reported that a Chinese familial AD pedigree with E22K mutation was associated with higher levels of serum H₂O₂ and lower activity of catalase (an H₂O₂ degrading enzyme) than controls. The binding of E22K to catalase caused more severe H₂O₂ accumulation in the brains of E22K-injected rats than in Aβ-injected rats. Moreover, H₂O₂ acted with E22K synergistically to induce higher cellular toxicity, more severe plaque deposition, increased neuron death, and more rapid memory decline than Aβ-injected rats. In conclusion, excess H₂O₂ may cause nerve damage by promoting the production of FA.

3.4 ROS Production from Cells in the Presence of Formaldehyde

Chen et al. found that intracellular reactive oxygen species (ROS) levels increased with elevated FA (Chen et al. 2017). FA-induced ROS was generated from eosinophils recruited to inflammatory sites in the airways (Jung et al. 2007). FA can trigger oxidative stress in cells and produce ROS during the culture. Cells such as bEnd.3 and N2a cells (1 × 10⁶) were plated in the 60 mm tissue culture plates. After 12 h of incubation, the cells were treated with 0.2 mM FA, followed by staining with DCFDA dye, and ROS content was analyzed by flow cytometry, as shown in Fig. 16.1b (Chen et al. 2017).

3.5 Culture of Cells in the Presence of Formaldehyde at the Pathological Concentration

Previous studies (Petro and Schengrund 2009; Lu et al. 2013b) have reported that concentrations of FA used in cell experiments were much higher than those detected in AD patients and normal individuals. To evaluate the effect of exposure to a pathological dose of FA (Li et al. 2016b), N2a cells were maintained in the cell culture medium with the presence of a low concentration of FA (Sigma-Aldrich, St. Louis, MO, USA) by using a serial passage strategy. To simulate the chronic exposure to the pathological dose of FA, cells were seeded into 100 mm petri dishes at 5 × 10⁵ cells/milliliter (mL) in 8 mL of cell culture medium (4 × 10⁶ cells), which was supplemented with FA (10 μM as the final concentration) in the medium. Fresh cell culture media were inoculated and collected. Cells were passaged every day for the following 6 days or longer. The medium containing FA was collected before the passaging. After trypsinization, aliquots of cell samples were harvested, and cells (4 × 10⁶) were seeded into a new 100 mm petri dish with 8 mL of medium containing FA (Fig. 16.2). Control cells were serially passaged in cell culture medium without the addition of FA (Wang et al. 2017).

Fig. 16.2

Cell culture in the presence and absence of FA. N2a cells were inoculated at a seeding density (5 × 10⁵ cells/mL) and cultured in the presence of FA (final concentration, 10 μM) for 24 h, after which aliquots were taken for another inoculation at the same seeding density and in the presence of the same concentration of FA. This culture procedure was then continued until the end of day 6. Aliquots were collected daily for the analysis as indicated. (Wang et al. 2017)

3.6 Formaldehyde-Induced Tau Protein Aggregation in Liquid–Liquid Phase Separation

As shown in the experiment in vitro observed by atomic force microscope (AFM), tau protein assembles into a soluble globule-like state. These observations suggest possible liquid–liquid phase separation (LLPS) between the globule-like assembly and their solvent (Nie et al. 2007a). It was still not observed that FA-induced tau protein forms fibrillary filaments in the solution. The results from other methods employed also indicate tau aggregation features in LLPS in the presence of FA (Nie et al. 2007b). The FA-induced LLPS of tau protein showed its toxicity to SH-SY5Y cells in culture.

4 Production of Formaldehyde from Animal Tissues

4.1 Formaldehyde from Frozen Fish

Under low temperatures, the storage of fish meat is often followed by the production of FA, which results from the oxidation of trimethylamine. FA is produced during frozen storage of gadoid (Atlantic cod, Gadus morhua; cusk, Brosme brosme; pollock, Pollachius virens; and silver hake, Merluccius bilinearis) fillets at −5 °C, resulting in similar reductions in the extractable proteins. Importantly, even at low temperatures, FA production remains a concern in fish storage (Bernheim 1973; Tokunaga 1974).

4.2 Formaldehyde in Brain Tissue

Neural cell death or loss of neurons is one of the pathological characteristics of AD. Cytotoxicity resulting from Aβ deposition and tau hyperphosphorylation leads to neurodegeneration and cell death by means of a process called apoptosis (Gandia et al. 2006). Loss of synapses in the affected brain regions shows the strongest correlation with cognitive impairment in AD patients and has been considered an the early mechanism that precedes neuronal loss (Tönnies and Trushina 2017). The concentrations of FA in the parietal lobe, frontal lobe, temporal lobe, occipital lobe, hippocampus, cerebellum, and brainstem of porcine brain were measured (25 °C) by DNPH-HPLC as described previously (Su et al. 2011).

4.3 Decomposed Brain Tissues Producing Formaldehyde

Brain tissues maintained at room temperature produce FA. Fresh porcine brain from a meat processing plant in Beijing was allowed to stand at room temperature (25 °C). Aliquots of the brain tissue were taken at different time intervals for measurements of the concentration of FA (Fig. 16.3a) by DNPH on an HPLC as described previously (Su et al. 2011), and compared with the standard curve of FA concentration (Fig. 16.3b).

Fig. 16.3

Changes in concentrations of FA in porcine brain at room temperature. A piece of fresh porcine brain (10 g) from a meat processing plant in Beijing was allowed to stand at room temperature (25 °C), and aliquots (1 g) of the brain tissue were taken at different time intervals for measurements of FA (panel a). FA was determined by DNPH-HPLC as described (Su et al. 2011), compared to the standard curve of concentration of FA solution (panel b). FA concentration was expressed in μmol per kilogram of fresh brain tissue. Data were from five separate experiments. ***p < 0.001. (Su et al. 2011)

4.4 Learning Activity Induces Generation of Brain Formaldehyde

Ai et al. examined changes in the hippocampal FA concentration after spatial learning activity in Morris water maze (MWM) in the wild type adult male Sprague−Dawley (SD) rats. The FA content in brain tissue was approximately 30 μM on day 1 and approximately 50 μM on day 6, as quantified by HPLC using a fluorescence detector. That hippocampus-related spatial learning activity elicits an elevation in hippocampal FA levels suggests FA-regulated NMDA-R most likely controls memory formation (Ai et al. 2019).

4.5 Formaldehyde in Urine

Urine-based FA has been reported as a potential biomarker for AD (Tong et al. 2011). Wang et al. recruited subjective cognitive decline (SCD, n = 110), objectively defined subtle cognitive decline (Obj-SCD, n = 140), mild cognitive impairment (MCI, n = 171), AD dementia (n = 136), and 72 cognitively normal controls (NC) participants. Then they determined the FA concentration in morning urine samples by HPLC column. The urine FA levels showed a trend of first increasing in SCD, followed by a further rise in Obj-SCD, and finally increasing in MCI and AD period (Wang et al. 2022a).

4.6 Formaldehyde from Intestinal Microbiota

Microbial models are used for the production of FA, such as the Porphyromonas gingivalis vimA mutant during hydrogen peroxide-induced oxidative stress (McKenzie et al. 2015; Hu et al. 2016) and FA dismutase in Pseudomonas putida J3 (Blaschke et al. 2017). In this chapter, literature on bacteria and fungi producing FA was not described in detail (Liu et al. 2017). The yield of FA was detected in the cecum of APP/PS1 transgenic mice and human stool (Chap. 7).

4.7 Intestinal Extension of Aging Mice

The intestine length of 129S2/SvPasCrl mice changed from adulthood to old age, particularly of the small intestine, which becomes longer in aged mice than young adults (Mou et al. 2021). Similar results were obtained with C57BL/6 mice (our unpublished data), appearing as a general phenomenon that the intestinal length becomes longer as aging.

5 Animal Models

5.1 Aged Rodents

5.1.1 Production of Formaldehyde in Aging Mice

Aging is the greatest risk factor for age-related memory decline. Therefore, an aged C57BL/6 mouse (wild type) can be directly used as an elevated FA model. As described by this laboratory, the level of brain FA in 10-month mice significantly increased, compared with those of 3-month mice (Li et al. 2016c). C57BL/6 mice were maintained under pathogen-free conditions (22 ± 2 °C, humidity 50%) and provided a regular diet and sterile water. Their brain FA concentrations were determined at different time intervals (3 months, 6 months, and 10 months) by using HPLC coupled with a chromogenic agent DNPH, as described previously (Su et al. 2011). The average concentration of brain FA in 10-month-old mice was significantly higher than that of 3-month-old ones.

5.1.2 Aged Rats

The concentration of endogenous FA in SD rats was measured at different ages. SD rats that were reared for 1 year had a significantly higher concentration of FA in the hippocampus than those for 1 month (Tong et al. 2013). This indicates that the level of endogenous FA in rodents increases with age, starting after 8 months of age. Mice and rats that were reared under normal conditions can be used to study the metabolism of endogenous FA when they are old enough naturally (Fei and Tong 2020).

5.1.3 Senescence-Accelerated Mice (SAMP8)

The senescence-accelerated mouse (SAM) is a model of accelerated senescence that established through phenotypic selection from a common genetic pool of the AKR/J strain of mice (Takeda et al. 1981; Takeda 1999). The SAM strain includes nine senescence-prone strains (SAMP) and four senescence-resistant strains (SAMR). The SAMP8 strain has been proposed as a model for studying human AD (Butterfield and Poon 2005), as it shows age-related learning and memory deficiencies in behavioral tests (Miyamoto et al. 1986; Carp et al. 2000). Hyperphosphorylation of tau protein was observed in SAMP8 (Morley et al. 2012). In comparison, the SAMR1 strain, which is commonly used as a control, has a normal lifespan and displays no distinct cognitive disorders.

As reported previously, SAMP8 displays impaired spatial learning abilities as early as 3 months of age (Chen et al. 2004). Three-month-old SAMP8 showed spatial cognitive decline, whereas 3-month-old SAMR1 did not. An imbalance in the cellular activities/expression levels of the enzymes SSAO and ADH3 results in FA accumulation in the brain of SAMP8, but the imbalance was not observed in SAMR1 control mice (Qiang et al. 2014). This suggests that the imbalance of FA metabolism is related to cognitive impairments in 3-month-old SAMP8 mice. The capacity for spatial learning and memory in 3-month-old SAMP8 mice was lower, while brain FA levels were higher, compared with age-matched SAMR1 mice. To clarify the underlying reasons for FA elevation in neurodegenerative diseases, Qiang et al. detected the expression level of (anabolic) semicarbazide-sensitive amine oxidase (SSAO) and (catabolic) alcohol dehydrogenase III (ADH3), which are involved in FA metabolism. As a result, levels of SSAO expression were increased, while ADH3 levels were reduced at the mRNA, protein, and enzymatic activity levels in 3-month-old SAMP8 mice. The imbalance of these metabolic enzymes may represent an explanation for the FA elevation in the SAMP8 brain (Fig. 16.4). Such an increase may be related to tau hyperphosphorylation in the brain, ultimately leading to cognitive impairment. SAMP8, as a classical AD mouse model, helps reveal the underlying mechanisms of age-related accumulation of FA.

Fig. 16.4

A hypothetical mechanism of FA accumulation as observed in SAMP8. A hypothetical mechanism for FA accumulation in 3-month-old SAMP8 (panel a) compared to age-matched SAMR1 (panel b) (He 2017)

5.1.4 AβPPLon/Swe Mice

Brain FA levels in AβPPLon/Swe transgenic mice were significantly related to the progression of memory decline. Memory recovery of these transgenic mice was also associated with FA reduction. These findings may provide valuable insights into the endogenous FA underlying mechanisms of cognitive impairment.

5.2 Animals Exposed with Formaldehyde

5.2.1 Formaldehyde Steaming Contacted Rodents

Exposure to gaseous FA led to an increase in its concentration (Cui et al. 1996). FA, as the smallest aldehyde molecule, can pass through the blood-brain barrier after dissolving in blood (Shcherbakova et al. 1986). Results from rat experiments showed that FA (administered intraperitoneally (i.p.) for 10 days) induces oxidative damage in frontal cortex and hippocampal tissues damage (Gurel et al. 2005). The number of hippocampal neurons decreased in the brains of rats exposed to FA, and further caused memory loss and cognitive decline. Different concentrations of gaseous FA exposure caused different effects on cognitive ability, anxiety, and depression-like behaviors which may be associated with changes in hippocampal glucocorticoid receptors and brain tyrosine hydroxylase levels (Li et al. 2016c).

As described by Li et al., different concentrations of evaporated FA were generated in static wood toxication chambers. Each cage housed a group of five mice during each FA inhalation treatment. The concentration of gaseous formaldehyde was monitored by a FA digital electrochemical analyzer (DM100-CH₂O), and was found to be approximately 1 ± 0.04 ppm and 2 ± 0.12 ppm during the procedure. Similar to the situation in humans, the mice were exposed to gaseous FA and they were affected as gas dissolved into their body fluids. The inhalation groups were exposed to different concentrations of gaseous FA (2 h once daily for 7 days). The animals were not allowed to drink or eat during exposure. The concentration of gaseous FA generated from chamber emissions was measured three times daily. The designed concentrations (0, 1 and 2 ppm) were close to experimental results (0, 1 ± 0.04 and 2 ± 0.12 ppm). Gaseous FA levels from the chamber were steady and reliable (Li et al. 2016c).

5.2.2 Intracerebroventricular Injection to Study Memory Impairment in the Presence of Formaldehyde

Intracerebroventricular injection (i.c.v.) is much more precise and requires much smaller quantity of FA to deliver it into the animal brain than intraperitoneal injection. First, the rats were anesthetized with sodium pentobarbital (45 mg/kg, i.p.) and placed into a stereotaxic apparatus during the operation. PBS (2.5 μL) or FA (0.1, 1, or 10 μmol) was injected into the bilateral ventricles according to the coordinates (anterior/posterior, 1.4 mm from bregma; medial/lateral, 1.8 mm; and dorsal/ventral, 3.0 mm). Micropump controlled the injection at a rate of 0.5 μL/min. The injection cannula was allowed to remain in the place for an additional minute before being removed to ensure the delivery of the entire injection.

Acting as an endogenous neuromodulator, hydrogen sulfide (H₂S) facilitates the induction of hippocampal long-term potentiation (LTP), which is involved learning and memory. Tang et al. performed injection (i.c.v.) to observe the effect of FA on learning and memory and endogenous H₂S generation in the rat hippocampus. FA can disturb the endogenous H₂S generation in the hippocampus, resulting in the oxidative stress-mediated neuronal dysfunction and impairment of learning and memory (Tang et al. 2013; Li et al. 2020).

5.2.3 Intracerebroventricular Injection to Induce LTP and Spatial Memory Decline

To study the effect of FA on LTP and long-term depression (LTD), Tong et al. injected SD rats (i.c.v.) with different concentrations of FA (in saline, 0.3 and 0.5 mM, 5 μL for each injection, i.c.v. in 5 min) followed by high-frequency electrical stimulation (HFS) for 30 min, after which the rats underwent either hippocampal FA detection or electrophysiological experiments (Tong et al. 2013). The injection with FA interferes the formation of LTP and spatial memory process. In the male SD rats that were injected (i.c.v.) with FA (0.3 and 0.5 mM, 5 μL, i.c.v. in 5 min), the hippocampal formaldehyde level rose 30 min after injection, and the field excitatory postsynaptic potential (fEPSP) amplitude was markedly reduced. These data demonstrate that excess hippocampal FA can inhibit the LTP formation in SD rats.

5.2.4 Intraperitoneal Injection

Formaldehyde Injection for Seven Consecutive Days to See Acute Effect

The male wild-type SD rats (250–300 g) were intraperitoneally (i.p.) administered with 0.5 mM FA (60 mg/kg, daily) prior to MWM training, and then subjected to learning and memory behavioral tests, followed by FA level detection. After that, the rats treated with FA (0.5 mM, i.p., 7 days) showed significant spatial learning function impairments in the MWM test (Tong et al. 2013; Huang et al. 2020). At the same time, memory retrieval ability was markedly reduced, along with increased hippocampal FA levels. These results demonstrate that excess hippocampal FA is capable of inhibiting spatial memory formation in SD rats.

Effect of Formaldehyde Accumulation by Injection for 30 Days

Since age-related dementia involves a chronic gradual process, male wild-type SD rats were intraperitoneally injected with FA (i.p. 60 mg/kg) over a period of 30 consecutive days (Gurel et al. 2005; Tong et al. 2011). Their hippocampal FA concentrations were then determined by fluo-HPLC after the completion of the MWM test. The excess FA suppressing hippocampal LTP formation in vivo and disturbing the recovery ability of learning and memory was observed in the FA-treated group (Tong et al. 2013). The mechanism of suppressed the hippocampal LTP formation might result from the excess FA blocking the NMDA receptor, which is a critical molecule for LTP and memory formation.

5.2.5 Tail Intravenous Injection

C57BL/6N mice were maintained in animal facilities under pathogen-free conditions and were injected with FA (3.7 μg per gram of body weight) via the tail vein as described by Erkrath et al. (1981). For Western blotting, mouse brain tissues were homogenized in a lysis buffer and proteins were extracted. For immunofluorescence detection, mouse brains were fixed with 4% paraformaldehyde and 10-μM-thick sagittal frozen sections were prepared for immunohistochemistry. Using tail intravenous injection, tau hyperphosphorylation was observed in the hippocampus of mice (Lu et al. 2013a).

5.2.6 Drosophila on Formaldehyde Diet

Different proportions of FA were added to the Drosophila melanogaster’s food (Whittinghill and Lewis 1961), and the effects of FA on Drosophila’s lifespan and stress resistance were observed. The lifespan of female flies depended on the FA concentrations. About 0.037% FA could significantly extend the lifespan of female flies, whereas the higher concentrations of FA (≥0.185%) could significantly reduce the lifespan of both male and female flies. These Drosophila results provided a new way to study the molecular mechanisms of longevity and stress resistance in Drosophila (Li and He 2016).

5.3 Methanol Feeding

5.3.1 Mouse Drinking Water with Methanol

As described by Dorokhov et al. (2015), methanol is reliably found in just one of the major food groups, fruits and vegetables, where pectin chemically locks methanol safely, allowing it to passe through digestion but seldom be absorbed by the gut. As a precursor, methanol ingested in large quantities is metabolized first to FA and then to formic acid or formate salts, which are poisonous to the central nervous system and may cause blindness, coma, and death. Methanol is metabolized in the liver and brain, leading to chronic exposure to methanol, FA, and formic acid with respect to long-term and several age-related pathologies.

Memory-related behavioral changes in rats were connected to chronic oral administration and systemic FA exposure (Bhatt and Panchal 1992; Fei et al. 2021). Eight-week-old male Institute of Cancer Research (ICR) mice were fed with methanol solution (2% or 3.8%) for more than 6 weeks (Yang et al. 2014a). The results from experiments, such as the olfactory memory test, Y-maze spatial recognition memory test, and immunohistochemical analysis, showed that methanol feeding in mice leads to some AD-like symptoms, including tau hyperphosphorylation, hippocampal neuron loss, and cognitive impairments. These methanol-fed mice, as a comparatively simple and easily acquired animal model, may be helpful to the studies related to pathological features of AD, either as a stand-alone tool or in combination with other animal models.

However, administration of FA or methanol, either by oral intake or injection, did not induce the formation of senile plaques in the brain of wild-type mice. This may be due to the differences in gene sequence of APP between mice and humans. Recently, senile plaque (Aβ deposits) have not been clearly observed in the brains of wild-type mice, except the transgenic mice with the human APP gene.

5.3.2 Monkey Drinking Water with Methanol

To further study the important pathological features in AD, Yang et al. expanded their research to the nonhuman primates, young rhesus monkeys (Macaca mulatta, from 3 to 4 years) (Yang et al. 2014b). In this experiment, they chronically fed the male rhesus monkeys with 3% methanol ad libitum for 1–2 years. Then, behavioral tests including working memory assessments, and biochemical tests were conducted to evaluate their cognitive ability and on levels of age-related impairment markers (Yang et al. 2014b). In the variable spatial delay response tasks, the monkeys showed memory loss after methanol feeding. Simultaneously, tau hyperphosphorylation at residues T181 and S396 was detected in cerebrospinal fluid during feeding. Aβ deposition (the formation of senile plaque) was observed in the hippocampus and cerebral cortex, followed by significant increase of tau phosphorylated aggregates in monkey brains (Yang et al. 2014b). They observed that tau hyperphosphorylation in cerebrospinal fluid is showed in methanol feeding dependent manner. After the feeding ended, tau phosphorylated aggregates are still persistent for 6 months in the brain, indicating that methanol feeding causes a long-time pathological change. The use of methanol feeding in monkeys may provide an animal model to study the pathology and evaluate the efficacy of drug treatment for AD (Su et al. 2016).

5.3.3 Formaldehyde and Amyloid-β in CSF of Aged Monkey

A recent investigation showed that FA levels increase in the cerebrospinal fluid (CSF) of aging rhesus monkeys, and revealed a negative correlation between CSF FA and age-associated Aβ levels in aged monkeys (Li et al. 2020). That is to say, rhesus monkeys are not only good animal models for studying AD but also suggest that FA is an important factor in AD progression and may be a diagnostic indicator of this disease.

5.4 Transgenic Animal Models

5.4.1 Transgenic with APP/PS1

In transgenic AD animal models, increases in brain FA levels and the development of abnormal LTP were observed in both APP/PS1 transgenic and APP transgenic mice (Trinchese et al. 2004). APP/PS1 transgenic mice were known to start depositing Aβ in the brain at the age of 2 months and showed abnormal LTP as early as the age of 3 months. Tong et al. found that the brain FA level of APP/PS1 transgenic mice was significantly higher at 3 months than that of their respective age-matched controls during the initiation of Aβ deposits. It appeared that the increase in brain FA accompanied the initiation of Aβ deposits and the onset of abnormal memory in these transgenic mice (Tong et al. 2011). In APP transgenic mice, Aβ deposits begin at 6–7 months of age (Kawarabayashi et al. 2001). Interestingly, their brain FA level significantly increased at 6 months and became similar to that of the controls at 12 months. This suggests that the onset of Aβ deposits is followed by an increase in brain FA. Moreover, in both APP/PS1 (6 months old) and APP (12 months old) transgenic mice, brain FA levels were not significantly different from those of their respective age-matched controls, but more typical senile plaques were detected in the brains of these two transgenic types of AD mice (Trinchese et al. 2004; Karuppagounder et al. 2008). Fei et al. identified that FA cross-linked with the lysine 28 residue in the β-turn of Aβ monomers to form Aβ dimers, and then accelerated Aβ oligomerization and fibrillogenesis both in vitro and in vivo (Fei and Tong 2020).

5.4.2 Decrease of Formaldehyde Recovers Memory Deficit in AβPPLon/Swe Mice

Lu et al. found that changes in the FA levels were related to learning and memory in AβPPLon/Swemice. Resveratrol improves learning and memory by reducing FA levels at the early stages of the transgenic mouse model and could be considered as a supplement for elderly individuals at the early stages of AD. FA could be used as a biomarker to monitor the effects of AD treatment in animal models, and even in clinics in the future (Lu et al. 2021).

5.4.3 ADH3 Knockout in Drosophila

Nitric oxide (NO) plays a role in learning and memory, and ADH3 which is also named S-nitrosoglutathione reductase GSNOR/(ADH3) is a key protein in the regulation of NO metabolism (Liu et al. 2001). To study the relationship between NO metabolism and learning and memory, the expression of gene (FA dehydrogenase) fdh, a homolog to mammalian GSNOR, was modulated in Drosophila. Hou et al. observed that fdh overexpression resulted in denitrosation of multiple proteins functionally enriched in vesicle-mediated transport, which was related to learning and memory (Hou et al. 2011). Qiang et al. observed that decrease in ADH3 is closely associated with the increase in FA levels in SAMP mice exhibiting a decline in the ability of learning and memory ability, suggesting that an overdose of endogenous FA may affect animal cognition (Qiang et al. 2014; Su et al. 2016).

5.4.4 ADH3 Knockin Mouse

ADH3/(GSNOR) is a highly conserved bifunctional enzyme involved in FA detoxification and termination of nitric oxide signaling (Goto et al. 2015; Barnett and Buxton 2017). Chen et al. prepared the transgenic C57/BL6 mice with ADH3 and found that overexpression of ADH3 impairs their ability of cognition. GSNOR, a key protein S-nitrosation metabolic enzyme, is a potential target in age-related cognitive impairment. In contrast to the free radical theory of aging, NO signaling deficiency may be the main cause of this process (Zhang et al. 2017). On the other hand, overexpression of ADH3 results in low concentrations of FA, which acts as a donor of methyl groups for the methylation of DNA, RNA, and Histones in epigenetic functions. Tong et al. observed that excessive decreases in FA levels lead to a decline in learning and memory in SD rats (Tong et al. 2013). This is to say, deficiency of FA also affects cognitive ability.

5.4.5 Aldehyde Dehydrogenase and Related Enzyme Knockout Mice

Aldehyde dehydrogenase (ALDH) detoxifies acetaldehyde into acetate, which has been deeply studied because alcohol use is widespread and related to numerous diseases, including oral, colorectal, liver, pancreatic, aerodigestive, breast, and colon cancers (Matsumoto et al. 1989). ALDH also acts and convert FA to formic acid (Hedberg et al. 2001). Therefore, loss-of-function mutations in ALDH2 also lead to FA toxicosis. Chaudhry et al. revealed that ALDH2 deficiency enhances ethanol-induced disruption of intestinal epithelial tight junctions, barrier dysfunction, and liver injury in transgenic mice (Chaudhry et al. 2015). To demonstrate FA acting as a risk factor for AD, Ai et al. assessed the spatial memory behaviors of the transgenic mice in the MWM, and observed their escaping latency within each training day (Ai et al. 2019). Those 7-month-old Aldh2−/− mice had a significantly longer escape latency than the wild-type mice, showing a marked impairment in the ability of spatial learning (Ai et al. 2019).

Heit et al. have briefly described the transgenic mice with different types of ALDH (Heit et al. 2015). The knockout mouse models for enzymes metabolizing ethanol (ADH1, CAT, and CYP2E1), acetaldehyde (ALDH2, ALDH1A1, and ALDH1B1), and enzymes involved in GSH synthesis (GCLC and GCLM) were also more or less related to the FA metabolism. Some transgenic mouse models have been prepared as follows: Cyp2e1−/− (Lee et al. 1996), Adh1−/− (Molotkov et al. 2002), Aldh2−/− (Isse et al. 2002; Yu et al. 2009), Aldh1a1−/− (Fan et al. 2003), and Aldh2 conditional knockout mouse (Skarnes et al. 2011). These mice models are beneficial to understanding methanol and FA metabolism and resultant oxidative stress (Evans et al. 2016), which are primary pathogenic events mediating alcohol- or FA-induced cell dysfunction and abnormally neurobehavioral changes. Utilization of these models will provide valuable information about the fundamental mechanisms underlying not only ethanol and acetaldehyde but also methanol and FA toxicity (Heit et al. 2015).

5.4.6 Semicarbazide-Sensitive Amine Oxidase Knockout

Semicarbazide-sensitive amine oxidase (E.C.1.4.3.6.), which catalyzes the reaction of methylamine and polyamines to generate FA, is a family of enzymes that is expressed in both prokaryotes and eukaryotes. Large amounts of SSAO are localized in smooth muscle cells of blood vessels in mammals (Lewinsohn 1984). Yu et al. (2004) proposed that SSAO-mediated deamination may contribute to protein aggregation, senile plaque formation, and inflammation. Thus, SSAO could be involved in the pathophysiology of chronic vascular and neurological disorders such as diabetic complications, atherosclerosis, and AD. As reported earlier by Hernandez et al., SSAO levels increased in moderate-to-severe and severe AD patients (Hernandez et al. 2006).

Su et al. found that SSAO-KO rats showed an enhancement in the ability to learn and in memory capacity with decreased levels of FA in both the brain and urine (our unpublished data). As described by Gokturk et al., knockin transgenic mice have increased SSAO activity and mRNA expression. A specific aortic phenotype with a condensed and rigid vessel wall was observed in some of the transgenic mice, but wild-type animals did not display this phenotype (Göktürk et al. 2003). Transgenic mouse model may be of great value for increasing knowledge about the extent to which human SSAO contributes to vascular complications in diabetes. Furthermore, SSAO may be potentially used as a target to prevent the progression of such complications. In this lab, SSAO-KO rats and the transgenic rats showed a slower learning rate than the wild-type rats.

5.4.7 Methylase Knockout and Knockin

Experience-mediated DNA methylation is regulated by DNA methyltransferase (DNMT) activity, and is essential both for the initial formation of recent memory and for the long-term maintenance of remote memory. In mice, simultaneous knockout of DNMT1 and DNMT3a reduces global DNA methylation and disrupts memory acquisition and retrieval (Miller et al. 2008; Feng et al. 2010). Overexpression of DNMT3a in the hippocampus can reverse spatial memory deficits in aged mice (Oliveira et al. 2012; Su and Tsai 2012). As hypothesized recently, endogenous FA is involved in learning and memory process, in particular learning ability, because FA acts as a donor for the methylation of DNA, RNA, and histones. Homeostasis of endogenous FA metabolism may benefit from these methylations, which are involved in learning and memory (Tong et al. 2013).

5.5 Increase in Formaldehyde in Animal Administrated with Small Compounds

5.5.1 Intraperitoneal Injection of D-Ribose

Male C57BL/6J mice (8 weeks) were obtained from Vital River Laboratory Animal Technology Co. Ltd. (Beijing, China). They were intraperitoneally injected (i.p.) with D-ribose (rib, 3.2 g/kg/d), D-glucose (glc, 3.82 g/kg/d), or saline (0.9% NaCl in double-distilled water) as the control for 10 days. Blood FA levels were measured using HPLC with 1.0 g/l DNPH. The results showed that D-ribose-treated mice exhibited significantly (p < 0.05) elevated blood FA than the control group, while D-glucose treatment did not produce a statistically signification increase (p > 0.05). The typical pathological characteristics of AD could be observed such as cognitive impairment, Aβ deposition, tau hyperphosphorylation, and glia activation after mice had gavage of D-ribose for 6 months (Han et al. 2014; Wu et al. 2015).

In another animal experiment, the mice were randomly divided into three groups and received intraperitoneal injections each day for 10 days with D-ribose at a dose of 3.2 g/kg, D-glucose at a dose of 3.82 g/kg, or 0.9% saline as control after 1 week of acclimatization to the cages. All mice were maintained in animal facilities under pathogen-free conditions. The mice showed cognitive impairment accompanied by the deposition of advanced glycation end products (AGEs) in their brains (Han et al. 2011; Han et al. 2014).

5.5.2 Administration with Folic Acid

Both FA and folic acid are important components of one-carbon cycle, with folic acid being particularly essential for neural system development. To investigate the relationship between folic acid regulation and FA metabolism, we examined the effect of folic acid feeding on FA accumulation. According to the Picolab Mouse Diet 20 composition, standard mouse chow contains 2.9 mg/kg of folic acid. C57BL/6 mice were randomly divided to three groups: those fed with regular food supplemented with 0 mg/kg (blank control group), 2 mg/kg (normal dose group), and 10 mg/kg folic acid (high dose group) for consecutive 30 days, respectively. After that, mice were subjected to MWM test before the FA concentration test. Mice fed with different concentrations of folic acid showed no difference in spatial learning and memory abilities in the behavioral test. In other words, supplementation of folic acid could not improve learning and memory for the wild-type mouse (Fig. 16.5a, b). On the contrary, the brain FA concentration significantly (p < 0.01) increased in the 10 mg/kg group than that of control mice. However, the 2 mg/kg group showed no marked (p > 0.05) increase in FA, although the increased FA levels depend on the feeding amount of folic acid (Fig. 16.5c). To demonstrate the contribution of folic acid to FA production, mouse neuro-2a cells were cultured in a medium with or without folic acid for 24 h, and the FA released into the media was measured. As shown in Fig. 16.5d, FA level is markedly lower in the media without folic acid than that supplemented with folic acid. Folic metabolism is involved in FA formation. Excess intake of folic acid resulted in higher concentrations of FA formation in mice brains and neuronal cells. These results suggest that a long-term observation (longer than 6 months) of animal behavior, through feeding excess folic acid, should be conducted in the future.

Fig. 16.5

Dietary folic acid supplementation was found to elevate brain FA levels. In this study, C57BL/6J mice (n = 9) were divided randomly into three groups and were fed with chows (AIN93G) containing different concentration of folic acids (0, 2, 10 mg/kg) for 30 consecutive days. MWM was used to detect mice learning ability (panel a) and memory capacity (panel b) after 1 month of feeding. FA concentrations of mice brain were measured after the behavioral test (panel c). N2a cells were incubated in a medium with or without folic acid for 24 h (panel d); then media were collected. FA concentrations were measured as soon as possible. Data were shown as mean ± S.E.M., ** indicates p < 0.01, ***indicates p < 0.001 (He 2017)

5.6 Dehydration Producing Formaldehyde

5.6.1 Rodents Exposed of Less Water Intake Suffer from High Levels of Endogenous Formaldehyde

Chronic dehydration is regarded as a common symptom in patients with age-related cognitive impairment, particularly those with AD. Li et al. developed an animal model of chronic dehydration model using C57BL/6 mice administrated with water containing 4% NaCl for 3 months. This treatment resulted in elevated brain FA levels accompanied by an imbalance between SSAO and FA dehydrogenase 3 (ADH3) (Li et al. 2016a).

Mice on the 4% NaCl diet exhibited significantly reduced brain 5-hydroxytryptamine (5-HT) levels and demonstrated slower learning rates in the shuttle box behavioral test compared to water-fed controls. To demonstrate the relationship between FA dysmetabolism and 5-HT-mediated learning impairment, Li et al. intraperitoneally injected the mice with FA once daily for seven days (Li et al. 2016a). The FA-treated mice showed significantly decreased brain 5-HT levels and slower learning rates in shuttle box compared to control groups-those injected with 4% NaCl, which showed neither significant differences in 5-HT levels nor impaired cognitive behavior. Notably, that water deprivation of mice (wild-type C57BL/6) for three days leads to a significant increase in brain FA concentration (Li et al. 2016a), demonstrating that both chronic and acute dehydration can induce high levels of endogenous FA, especially brain FA.

5.6.2 Determination of Endogenous Formaldehyde in Humans Subjected to Water Deprivation

As described by Li et al., the volunteer participants (n = 20) followed activity protocols according to the study’s recruitment requirements (Li et al. 2016b). Urine samples (middle stream) were collected in the morning before breakfast (8:00 a.m.), before lunch (12:30), and before going to sleep (11:00 p.m.) to measure the urine formaldehyde (FA/Urc ratios). The participants were divided into three groups: (1) a water-restricted group, (2) a prescribed water intake group, and (3) a control group maintaining habitual water consumption. Measurements were carried out to compare the FA concentrations between the water-deprived group and the water-prescribed group. The results showed that lack of water intake could lead to FA accumulation in vivo, highlighting the importance of maintaining adequate water intake in daily life (Li et al. 2016b; Kou et al. 2022).

6 Estimating Neuropsychiatric Disorders Related to Formaldehyde

6.1 Endogenous Formaldehyde

In a clinical study, we measured endogenous FA levels and cognitive abilities of the AD patients compared with those of age-matched controls (Tong et al. 2011; Li et al. 2016b). Cognitive function was assessed using two screening tests: the mini-mental status examination (MMSE) and the Montreal cognitive assessment (MoCA). The second method to assess a patient’s mental status involves using specific neuropsychological tests that focus on particular domains of cognition, such as frontal executive functions, attention, episodic verbal and visuospatial memory, declarative knowledge such as language (speech, reading, and writing) and arithmetical, as well as visuospatial and perceptual abilities (Finney et al. 2016). Data were analyzed using stepwise linear regression (Kilburn et al. 1998). Neurobehavioral assessments included tests of balance, reaction time, strength, hearing, visual performance and cognitive recall, perceptual-motor function, and memory.

Regression equations were used to model test performance and the influences of demographic factors (Kilburn et al. 1998). Clinical symptoms include excessive fatigue, somnolence, headache, difficulty remembering, irritability, and mood instability, prolonged choice reaction time, delayed blink latency, abnormal balance, ﻿constricted visual fields, delayed verbal recall and visual reproduction were impaired, errors on fingertip number, abnormal writing, prolonged choice reaction time, decreased long-term memory, and other cognitive deficits (Kilburn 1994). In animal studies, FA exposure induced cognitive and memory impairments as demonstrated through open field, water mirror maze (Pitten et al. 2000; Malek et al. 2003), new object recognition, and other behavioral assessments (Lu et al. 2008; Li et al. 2016c). Based on these findings, Chen et al. prospected the potential diagnostic accuracy of urine FA levels in AD through a systematic review and meta-analysis (Chen et al. 2022).

6.2 Endogenous Formic Acid

Formic acid is one of the FA intermediate products in the metabolic pathway process to carbon dioxide and water, in which tetrahydrofolic acid is required and consumed. Formic acid is relatively stable compared with FA in vivo. Thus, a recent systematic evaluation indicated urinary formic acid as a new potential biomarker for AD (Wang et al. 2022b). Here, we suggest that the simultaneous detection of FA and formic acid will lead to more reliable results in assisting in the diagnosis and monitoring of clinical effects in the treatment of AD.

7 Conclusion

To comprehensively study the effects of FA on organisms, diverse experimental models should be established to account for both high and low concentrations, as FA metabolism involves multiple metabolic pathways (see Chap. 2). Alongside research on the relationship between FA and neurodegeneration, increasingly molecular, cellular, animal models, and clinical applications have been performed in different patterns and methods. Maintaining the homeostasis of endogenous FA is crucial, as its excess or deficiency can disrupt gene regulation, protein expression, and neural functions.

Since rodents metabolize FA more efficiently than humans, cognitive data from mice and rats cannot be directly referred to humans. Studies in mice demonstrate that Aβ deposition in the brain by inactivating FA dehydrogenase. Administration low concentration (3%) of methanol for at least 6 months or longer in young monkeys induces a decline of working memory ability and tau hyperphosphorylation at T181 and S396 in cerebrospinal fluid and phosphorylated tau aggregation in the hippocampus and cerebral cortex. As shown in clinical investigations, levels of FA and formic acid are positively related to the severity of illness in age-related cognitive impairment. These molecular, cellular, animal, and clinical models support the investigation of the pathomechanism and evaluate the efficacy of lifestyle interventions and drug treatments for AD (Su et al. 2016).

Acknowledgments

All grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_17

17. Methods in Determination of Formaldehyde

Xiangpei Yue¹, Tao Su² and Rongqiao He2  

(1)

Beijing Institute of Basic Medical Sciences, Beijing, China

(2)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

In order to analyze formaldehyde, the simplest aldehyde closely related to human health from both exogenous and endogenous surroundings, many methods have been developed and employed with different techniques and instruments. In fact, measurements by different methods result in different values for the concentration of exogenous and endogenous formaldehyde. Among the methods, high-performance liquid chromatography (HPLC) is one of the most commonly used approaches in the determination of formaldehyde in the liquid and body tissues such as urine, blood, the brain, and liver. HPLC and gas chromatography (GC) coupled with mass spectrometry (MS) or fluorescent techniques show their high sensitivity and advantages. 2,4-Dinitrophenylhydrazine (DNPH) is one of the most frequently used reagents applied with spectrophotometer, HPLC, and GC. HPLC coupled with DNPH or ampicillin has been used to determine formaldehyde levels of the morning urine from Alzheimer’s disease (AD) patients and age-matched participants. The results showed a positive correlation between the levels of urine formaldehyde and the severity of cognitive impairment in the AD patients. Approximately 40% of the AD patients have got high levels of endogenous formaldehyde, suggesting that endogenous formaldehyde can be developed as a biomarker for progression and intervention of AD. Currently, the specific fluorescent probes such as formaldehyde probe-1 (FAP-1) and formaldehyde-induced 2-aza-Cope reaction have been synthesized to label formaldehyde molecules in cells. In particular of using these fluorescent probes, the endogenous formaldehyde is found to be localized in organelles such as lysosomes and mitochondrion. Exogenous formaldehyde is also localized and restricted in lysosome inside a living cell monitored by confocal microscopy. Furthermore, nano-techniques have been also introduced to analyze formaldehyde. Quartz crystal microbalance (QCM) can measure nanogram-scale changes of formaldehyde. As the technique advances, current efforts are underway to develop greater sensitivity, lower cost, improved portability, and more straightforward detection methods. The operational principles and sensing performance of sensors have been created as well, and the convenient and high-performance formaldehyde-determining applications will appear more in the near future.

Keywords

FormaldehydeGenerationMetabolismFormaldehyde dehydrogenase

Abbreviations

A

AD

Alzheimer’s disease

ADI

Acceptable daily intake

ASTM

American Society for Testing Materials

D

DDL

3,5-Diacetyl-1,4-dihydrolutidine

DNPH

2,4-Dinitrophenylhydrazine

E

EPA

Environmental Protection Agency

F

FAP-1

Formaldehyde probe-1

G

GC

Gas chromatography

GC-MS

Gas chromatography-mass spectrometry

H

HPLC

High-performance liquid chromatography

I

IARC

International Agency for Research on Cancer

M

MCI

Mild cognitive impairment

MS

Mass spectrometry

P

PET

Photoinduced electron transfer

Q

QCM

Quartz crystal microbalance

T

TiO₂-NTA

Titanium dioxide nanotube array

W

WHO

World Health Organization

1 Introduction

Abundant methods in analysis of formaldehyde have been established in the recent decades (Table 17.1). More attention is paid to formaldehyde, with which many human diseases are found to be related, especially the brain impairment and disorder. Recently, formaldehyde toxicity in age-related neurological dementia has been investigated (Kou et al. 2022). Formaldehyde, as a common environment pollutant, is widely used in industry to manufacture building materials and numerous household products, such as some plywood adhesives, abrasive materials, insulation insecticides, and embalming fluids. Formaldehyde is found everywhere from the air to water, from soil to natural food, from lotion to food preservatives, from skin care products to bacteria, and from digestion contents to intestinal microbiota (Liu et al. 2017) (see Chaps. 1 and 7). In other words, every organism including human beings is naturally producing formaldehyde at each moment through material metabolisms. In recent years, publics and government of many countries have paid more attention to formaldehyde as pollution becomes worse. Therefore, determination or analysis of formaldehyde becomes a process that has to be performed in our daily life. Different methods in analysis of formaldehyde have been developed, such as the fluorescent molecular probe (Tang et al. 2016a, b, 2020; Liang et al. 2017; Xu et al. 2018; Fu et al. 2019; Quan et al. 2022; Liang et al. 2023; Li et al. 2023), the nanoporous silica aerogel sorbent (Barkhordari et al. 2017), the titanium dioxide nanotube array (TiO₂-NTA) (Tang et al. 2017), the derivatization procedure adapted to high-performance liquid chromatography mass spectrometry/mass spectrometry (HPLC-MS/MS) (Backe 2017), and genetically encoded formaldehyde sensor (Zhang et al. 2020; Zhu et al. 2021). In this chapter, we would like to briefly introduce the methods in analysis of formaldehyde in vivo and in vitro.

Table 17.1

The formaldehyde detection methods

Authors/Year

Methods

Reagents

Samples (value)

Limit of detection

Sawicki et al. (1961)

Colorimetry

3-methyl-2-benzothiazolone

Hydrazone

Aqueous solution (90 μg/100 mL)

0.1 μg/mL

Lorrain et al. (1981)

Ion chromatography

–

–

0.5 nmol

Septon and Ku (1982)

Polarography

Analyzed by differential pulse polarography at a dropping mercury electrode

Workplace air range of 5.8–17.7 mg/m³

–

Szarvas et al. (1986)

Dimedone ¹⁴C radiometric method

5,5-dimethyl-cyclohexane-1,3-dione

Blood (0.4–0.6 g/mL); Urine (2.5–4.0 g/mL)

–

Pedrero et al. (1989)

Spectrophotometry

Pararosaniline

Formaldehyde in air (1.25 mg/m³)

0.1 μg/mL

Houlgate et al. (1989)

HPLC

2,4-dinitrophenylhydrazine

Mainstream cigarette smoke (5 ± 0.07 μg per cigarette)

–

Grömping and Cammann (1993)

Fluorimetric HPLC

2-diphenylacetylindan-1,3-dionhydrazine (DAIH), N,N-diphenyl-1-naphthylamine-5-sulfonhydrazine (DNSH), DDL, chromotropic acid (CTA), pararosaniline (PRA), DNPH

Candle smoke (DNPH 1.6 ppm; DNSH 0.5 ppm; DAIH 0.6 ppm; DDL 0.5 ppm; CTA 0.7 ppm; PRA 0.5 ppm)

2 ppbv, 0.5 ppbv, 1 ppbv, 5 ppbv, 50 ppbv, 10 ppbv

Sárdi and Tyihák (1994)

HPLC

Dimedone, methanol

Fresh animal tissues (e.g., liver, meat) or the fresh parts of plants

–

Shrivastaw and Singh (1995)

Spectrophotometer

Phenyl hydrazine (PH) and potassium ferricyanide (PF)

Diphtheria Tetanus Pertussis Vaccine (3.4 μg/mL), Diphtheria Tetanus Vaccine (3.96 μg/mL), Tetanus Toxoid Vaccine (0.61 μg/mL), Japanese Encephalitis Vaccine (8.10 μg/mL)

100 ng

Quesenberry and Lee (1996)

Spectrophotometry

Periodate, Purpald

Aqueous solution

1 nmol

Chan and Xie (1997)

Adsorption voltammetry

Girard’s reagent T, Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate

Air in chem Lab (4.8 μg/m³); Air in a newly reconstructed chem Lab (24.4 μg/m³)

0.7 ppbv

Ebeler et al. (1997)

Gas chromatography (GC)

–

Tumor-bearing mice (1.43–2.98 μM) and control mice (0.77–1.01 μM)

–

Possanzini and Palo (1997)

HPLC, Fluorimetric

2-Diphenylacetyl-l,3-indandione-l-hydrazone

Atmospheric formaldehyde (1–5 ppb)

0.25 ppbv

Bechmann (1998)

Flow Injection Analysis (FIA)

Enzymatic oxidation of formaldehyde

Mixture of fish tissue (17.67 ± 3.05 mg/kg)

–

Bolta et al. (1998)

Gas chromatography

2,4-dinitrophenylhydrazine

Spiked atmosphere (0.5 mg/m³)

Interior of new furniture (1.3 mg/m³)

0.17 mg/m³

Martos and Pawliszyn (1998)

Gas chromatography, mass spectrometry (MS)

O-(2,3,4,5,6-Pentafluorobenzyl) hydroxylamine hydrochloride (PFBHA)

Gaseous formaldehyde (640 ppbv)

4.6 ppbv

Karlberg et al. (1998)

Closed container diffusion (CCD) method

2,4-Dinitrophenylhydrazine

Cream base (2400 μg/g) diazolidinyl urea (350 μg/g) in shin-care products

0.06 μg/L

Komazaki et al. (1999)

HPLC

2,4-dinitrophenylhydrazine

Averaged concentrations in air in Kawasaki (7.7 ± 5.5 ppbv)

0.05 ppbv

Spanel et al. (1999)

Selected ion flow tube mass spectrometry

–

Patients with prostate cancer (0.83 μM) and bladder cancer (2.83 μM)

–

Rózyło et al. (2000)

HPLC-OPLC-MS

4,4-dimethyl-cyclohexane-1,3-dione

Teeth samples (0.05–0.40 μg/g)

–

Chan et al. (2001)

Spectrophotometry

3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH), iron(III) chloride–sulfamic acid solution

Indoor air (14.4 ± 1.5 μg/m³, 17.8 ± 2.4 μg/m³, 6.6 ± 0.9 μg/m³, 7.5 ± 1.2 μg/m³)

3 μg/m³

Luo et al. (2001)

HPLC

Ampicillin

Blood plasma (1.34 μg/mL)

0.46 μg/mL

Kato et al. (2001)

Preconcentration-chemical ionization mass spectrometry

–

Hela S3 cervical cancer, K562 leukemia, and MCF-7 breast cancer cell lines (1.5–4.0 μM)

–

Iványi et al. (2002)

HPLC

2,4-dinitrophenylhydrazine

Shampoo (0.038 g/100 mL)

4 × 10⁻⁶%

Maboudou et al. (2002)

GC-MS

Sigle ion monitoring (SIM)

Rat brain (10–900 ng/mL)

20 ng/mL

Yu et al. (2003)

HPLC/electrochemical

Dopamine, DNPH

Mouse liver, kidney, and brain tissues 63, 51, and 11 nmol/g

–

Li et al. (2004)

Flow-injection chemiluminescence

Potassium bromate, rhodamine 6G

Formaldehyde in air sample (0.097 [±2.5%], 0.256 [±1.7%], 0.139 [±2.4%], 0.305 [±2.0%] mg/m³)

0.3 μg/L

Rivero and Topiwala (2004)

Combined solid-phase microextraction–isotope dilution mass spectrometry

Pentafluorophenylhydrazine (PFPH)

Formaldehyde standard solution (4 μg/mL)

0.39 μg/L

Motyka and Mikuska (2004)

Fluorescence;

2,4-pentandione

Indoor air (27.2 ± 0.4 μg/m³)

1.6 μg/m³

Burini and Coli (2004)

HPLC and diode-array detection (DAD)

Ethyl 3-oxobutanoate and ammonia

Spirits sample (ranged between 0.27 and 3.01 mg/L)

0.024 μg/mL

Sritharathikhun et al. (2005)

Flow injection technique with spectrophotometric and fluorometric detection

Acetylacetone

Indoor air 5.14 ± 0.08 ppbv for 20 mL of the air sample

Spectrophotometric (0.6 ppb) and the fluorometric (0.2 ppb)

Mariscal et al. (2005)

Fluorescence

–

Cotton (1.27 ± 0.20 μg/cm²)

Filter paper (1.67 ± 0.290 μg/cm²)

Polyvinyl chloride (0.30 ± 0.12 μg/cm²)

Silicone-coated (0.49 ± 0.14 μg/cm²)

–

Tomcík et al. (2005)

Interdigitated microelectrode array

BrO⁻

Textile pieces samples A, B, C, D (207, 240, 353, 400 mg/kg)

4 × 10⁻⁶ Mol/dm³

Bertoni et al. (2005)

Column liquid chromatography, ultraviolet (UV) detection

1-Methyl-1-(2,4-dinitrophenyl) hydrazine

Sampling rate for formaldehyde, 15.0 mL/min

0.2 ppbv in 100 liters air sample

Liu et al. (2005)

Liquid-phase microextraction coupled with HPLC

2,4-dinitrophenylhydrazine

Shiitake mushroom (355 ± 15 μg/g)

5 μg/L

Largiuni et al. (2005)

Spectrofluorimetric

Acetylacetone, acetic acid, and acetate

Seawater (mean 15 mg/L)

0.7 mg/L

Li et al. (2005)

Spectroscopy

2,4-Pentanedione

Formaldehyde concentrations are higher at lower altitudes 60 m (3.5 ppbv), dropped to near zero at 750 m and 1500 m

Aqueous (16 nM), gaseous (70 pptv)

Kawamura et al. (2005)

Formaldehyde gas sensor

4-Amino hydrazine-5-mercapto-1,2,4-triazole (AHMT)

Air from living and dining rooms and kitchen (0.017 ppm), and air from bedroom (0.007 ppm)

0.04 ppm

Motyka et al. (2006)

Chemiluminescence flow method

Gallic acid, hydrogen peroxide in an alkaline solution

Formaldehyde in air; the calibration graph is linear up to 300 μg/m³ (244 ppb)

0.60 μg/m³ (0.49 ppb)

Zhao et al. (2006)

Staircase voltammetry

Electrocatalytic oxidation of Formaldehyde, Ni(III)

The linear range of detection is from 46.8 to 1640 μg/L (7.80 × 10⁻⁷ M)

23.4 μg/L

Motyka et al. (2007)

Chemiluminescence

Gallic acid, hydrogen peroxide

Rainwater sample (7.61 ± 0.02 μmol/L, 1.58 ± 0.08 μmol/L, 1.92 ± 0.09 μmol/L, 9.83 ± 0.05 μmol/L, 0.90 ± 0.08 μmol/L)

4 × 10⁻⁸ M.

Wang et al. (2007)

Colorimetric

Acetylacetone

The linear range (0.8–20.0 μg/mL)

0.8 μg/mL

Takigawa et al. (2007)

Headspace gas chromatography

O-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine

Urine from healthy individuals ranges (1.89–4.81 μM)

1.08 μg/L

Bianchi et al. (2007)

Solid phase microextraction(SPEM)-GC-MS

Pentafluorobenzyl-hydroxyl-amine hydrochloride

Haddock (1.47 ± 0.27 mg/kg); Cod (106 ± 15 mg/kg); Hake (293 ± 26 mg/kg); Mullet (3.38 ± 0.71 mg/kg)

17 μg/kg

Cui et al. (2007)

Spectrophotometry

Rhodamine B, potassium bromate, sulfuric acid

Sea cucumber (12.3 ± 0.1 μg/kg); Bamboo shoot (23.6 ± 0.1 μg/kg); Sleeve-fish (86.0 ± 0.2 μg/kg); Tripe (36.1 ± 0.3 μg/kg); Mushroom (83.5 ± 0.2 μg/kg); Melon seeds (13.4 ± 0.1 μg/kg); Vermicelli (34.8 ± 0.2 μg/kg); Bean curd (67.2 ± 0.2 μg/kg); Confect (56.9 ± 0.1 μg/kg); Shrimp (24.9 ± 0.3 μg/kg)

2.90 μg/L

Abbasi et al. (2007)

Spectrophotometry

Janus green, bromate, sulfuric acid

Melamine-formaldehyde resin (6.5 ± 0.71% μg/mL)

Chemical industrial wastewater (0.70 ± 0.01% μg/mL)

0.0015 μg/mL

Trenholm et al. (2008)

Gas chromatography–mass spectrometry

PFBHA

Natural organic matter (NOM) reagent water (195 μg/L)

Wastewater matrix (760 μg/L)

10 μg/L

Chen et al. (2008)

Chromatographic

2,4-dinitrophenylhydrazine

Cotton (89.6 ± 2.1 mg/kg); Wool (45.5 ± 1.6 mg/kg); Cashmere (58.4 ± 1.2 mg/kg); Terylene (2.8 ± 0.2 mg/kg); Nylong (2.9 ± 0.1 mg/kg)

0.06 mg/kg

Soman et al. (2008)

HPLC-UV

2,4-dinitrophenylhydrazine (DNPH)

Three drug substances (Not detected, 0.4, 0.3 ppm)

0.03 ng (0.1 ppm)

Zhang et al. (2009)

Electronic nose analysis

–

Fresh octopus sample (20%, 10%, 5%, 2.5%, 1.25%, 0.625%, 0.313%, 0.156%, 0.0781%, 0.0391%, 0.0195%, and 0%, respectively)

–

Iqbal and Novalin (2009)

HPLC

2,4-dinitrophenylhydrazine, Ca(OH)₂, glycolaldehyde,

Aqueous solution (170 μmol/L)

–

Hill et al. (2009)

Colorimetric solid-phase extraction

Sodium hydroxide, Purpald

Solutions with formaldehyde concentrations up to 20 ppm

0.08 ppm

Weng et al. (2009)

Polydimethylsiloxane (PDMS) microfluidic chip

Acetylacetone

Shiitake mushroom (187.9 ± 30 mg/kg); Frozen catfish (28.2 ± 5.3 mg/kg); Pork (5.4 ± 1 mg/kg); Pear (47.6 ± 3.6 mg/kg); Codfish ball (28.4 ± 4.5 mg/kg); Dired shrimp (50.7.2 ± 10.1 mg/kg); Dried anchovy (25.5 ± 5.2 mg/kg); Ginseng (150.6 ± 20 mg/kg)

Food samples (5.0 mg/kg); standard formaldehyde solution (2.0 μg/mL)

Emeis et al. (2010)

¹³C NMR spectroscopy

–

Benzylhemiformal (0.37%); Diazolidinyl urea (0.29%); Imidazolidinyl urea (0.054%); N,N′-methylenebis (0.15%); Quaternium-15 (0.11%); Tris-hexahydrotriazine (0.019%)

0.01%

Wei et al. (2010)

Gas chromatography

DNPH

Engine exhaust formaldehyde (32.68 μg/L)

28.2 × 10⁻⁹ g/L

Wang et al. (2011)

Resonance fluorimetry

PY, KBrO3

Blood plasma samples (5.94 × 10⁻² μg/mL)

3.80 ng/ mL

Teshima et al. (2011)

Spectrophotometry

Hydroxylamine sulfate, iron(III)–ferrozine complex, hydroxylamine

Formaldehyde in industrial wastewater (157 ± 3.7 mg/L)

1.6 μg/L

Wang et al. (2012a)

Electro-spinning/netting nano-fiber/nets

Polyethyleneimine (PEI)-titanium(Tio₂) fibers on QCM

Gaseous formaldehyde (0–5 ppm)

50 ppb

Nengsih et al. (2012)

Spectrometry

Gold nanoparticles

Aqueous formaldehyde range(0–37%)

3%

Lefebvre et al. (2012)

HPLC

2,4-dinitrophenylhydrazine

Facial moisturizer (2.4 ± 0.5 μg/m³); body lotion (2.3 ± 1.0 μg/m³); Foundation (1.9 ± 0.4 μg/m³); Shower gel (2.0 ± 0.7 μg/m³); Shampoo (2.2 ± 0.7 μg/m³); Deodorant (2.7 ± 0.6 μg/m³); Hair conditioner (2.6 ± 0.6 μg/m³); Hair styling gel (2.5 ± 1.7 μg/m³)

0.07 μg/m³

Wang et al. (2012c)

HPLC

2,4-dinitrophenylhydrazine

Fruit juice samples, Tomato (27.1 ng/mL); Peach (19.7 ng/mL); Orange (24.0 ng/mL)

6.0 ng/mL

Arvand et al. (2012)

Ionic liquid-based dispersive liquid-liquid microextraction (DLLME)/spectrophotometry

Methyl acetoacetate, ammonia.

Shampoo-1 (75 ± 3.5 ng/mL); Shampoo-2 (50 ± 4.1 ng/mL); Textile industrial factory wastewater (6.0 ± 4.5 ng/mL); Wood and paper industrial factory wastewater (100 ± 3.0 ng/mL)

0.02 ng/mL

Wang et al. (2012b)

HPLC

2,4-dinitrophenylhydrazine

Beer samples (172–385 ng/mL)

0.6 ng/mL

Deng et al. (2012)

Electrochemiluminescence

Tris(2,2-bipyridyl)ruthenium(II), hexamethylenetetramine

Indoor air of new building (18.2–40.6 g/m³); Outdoor air of Seven Star Park and Guilin Sanjin pharmaceutical company were from 7.6 to 21.3 g/m³

0.15 μg/m³

Zali et al. (2013)

GC-MS

–

Diphtheria–tetanus (DT) antigen (2.9 × 10⁻³), DT vaccine (4.3 × 10⁻⁵), enterotoxemia (0.133%) (w/v%), black disease (0.130%), hemorrhagic septicemia (0.050%)

979 ng/L

Alizadeh and Soltani (2013)

Chemiresistor sensor

Chemically exfoliated graphene flakes, blended with poly(methyl methacrylate)

Formaldehyde concentration was linear between 0.05 and 5.0 ppm

10 ppb

Tian et al. (2013)

Pd-functionalized SnO₂ sensor

Pd-functionalized mesoporous SnO₂ fibers

Formaldehyde gas in air (200 ppm)

50 ppb

Yeh et al. (2013)

GC-MS

2,4-dinitrophenylhydrazine

Shredded squid 1 (22.3 mg/kg)

2.0 mg/kg

Kleinnijenhuis et al. (2013)

HPLC-MS

2,4-dinitrophenylhydrazine

Average formaldehyde concentration in rat blood was 2.3 mg/L

0.015%

Jiang et al. (2013)

Chromatographic and mass spectrometer

Purpald, alcohol oxidase

The range of formaldehyde (0.02—0.8 mM)

5 μM

Monakhova et al. (2013)

¹H NMR spectroscopy

–

Hair straightening products (0.42–5.83%)

0.14%

Maneli et al. (2013)

HPLC

2,4-dinitrophenylhydrazine

“Brazilian keratin type” hair straightening products (0.96–1.4%)

6 ppb

Sassine et al. (2014)

Colorimetry

2,4-dinitrophenylhydrazine

Formaldehyde in air sample (6.4 ± 0.7 ppbv, 14.6 ± 1.7 ppbv)

4 pptv for 100 cm

Yu et al. (2014b)

Colorimetry

Single-crystal-to-single-crystal fashion (Cu(I)-MOF)(1-benzimidazolyl-3,5-bis(4-pyridyl)benzene, MOF)

The range of formaldehyde (0.0016–1.6 ppm)

0.016 ppm

Li et al. (2014)

DOAS (a differential optical absorption spectroscopy)

–

Formaldehyde concentrations in Shanghai ambient air at a research station in Fudan University, April 2010–April 2011

1.0 ppb

Toda et al. (2014)

Continuous flow fluorometry

10 mM H₂SO₄

0.01 M 2,4-pentanedione (PD)，0.25 M acetic acid, and 2 M ammonium acetate

In forest air, particulate formaldehyde (0.18 μg/m³); gas formaldehyde (3.9 μg/m³)

0.048 μg/m³ (g) and 0.0033 μg/m³ (p)

Zhang et al. (2014)

Spectroscopy

MBTH, NH₄Fe(SO₄)₂, H₂O, Au/SiO₂ colloids

Fresh squid and shrimp samples (0.13–0.21 mg/kg)

0.17 mg/L

Tang et al. (2014)

Spectrophotometry

Eosin Y, potassium bromate, phosphoric acid

Shrimp (8 ± 0.5 μg/g), Yuba (25 ± 0.3 μg/g), Shiitake (19 ± 0.7 μg/g)

0.00988 μg/mL

Chen et al. (2014)

Gas sensor

Zeolitic imidazolate framework (ZIF)

Range of formaldehyde concentration (5–500 ppm)

5 ppm

Ueta et al. (2015)

HPLC

2,4-Dinitrophenylhydrazine

Real indoor air samples (14.7 ng/L; 15.7 ng/L; 17.4 ng/L)

2.5 ng/L

Jeong et al. (2015)

Gas chromatography-mass spectrometry

O-(2,3,4,5,6-pentafluoro-benzyl)-hydroxylamine hydrochloride

Herb wine (74.70 ± 5.12 ng/g); apricot liqueur (56.81 ± 5.47 ng/g); Beer (45.47 ± 1.93 ng/g); Red wine (40.90 ± 2.69 ng/g); White wine (18.38 ± 1.34 ng/g); Sparkling wine (19.50 ± 0.17 ng/g); Whisky (782.10 ± 6.10 ng/g)

0.01 mg/L

Fang et al. (2015)

Gas-sensing performance

Ag-modified In₂O₃/ZnO nanobundles

Range of formaldehyde concentration(0.1–1.6 ppm)

100 ppb

Monkawa et al. (2015)

Spectrometry

4-[3-(2-methoxy-4-nitrophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate sodium salt (WST-8), formaldehyde dehydrogenase(FALDH), NAD⁺, EDTA

Water (0.005–0.5 ppm); gas (5–80 ppb)

15 ppb (water)

1.5 ppb (gas)

Wong et al. (2015)

Visual detection

Resin-linked sterically bulky amines, fluorescent alkynes

Formaldehyde concentration (0–1000 ppm)

10 ppm

Galli et al. (2015)

HPLC

Acetonitrile HPLC gradient-grade and hydrochloric acid, 2,4-dinitrophenylhydrazine

Determined concentrations ranging from 0.0036 to 0.184%

0.41 g/mL

Tang et al. (2015)

Spectrophotometric

Malachite, Green, potassium bromate, sulfuric acid

Tap water (0.2 ± 0.02 μg/g), Coca-cola (0.5 ± 0.07 μg/g), Shiitake (18.5 ± 0.05 μg/g)

1 ng/mL

Brewer and Chang (2015)

Fluorescent probe

2-aza-Cpoe-based trigger of FAP-1

Determined concentrations range in HEK293T cell

5 μM

Yang et al. (2016)

Spectrometry

G-quadruplex DNAzyme and 2,2,-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), H₂O₂

Indoor air (0.12 mg/m³)

0.01 mM

Yanaga et al. (2016)

Fluorometric approach

10 μmol/L indigotrisulfonate (ITS), 10 mmol/L H₂SO₄

0.01 mol/L 2,4-pentanedione, 0.25 μmol/L, acetic acid, 2 μmol/L ammonium acetate

Formaldehyde concentration (0–1200 ppbv)

0.3 ppbv

Xu et al. (2016)

Naphthalene-based fluorescent probe (AENO)

6-(1-aminobut-3-en-1-yl) naphthalen-2-ol

Concentration of formaldehyde in HeLa cells (209 μM)

0.57 μM

Tang et al. (2016a)

Fluorescent probe

1,8-naphthalimide, hydrazine

Lysosomes in the living HeLa cells

5.02 × 10⁻⁶ M

Tang et al. (2016b)

Fluorometry

Tow-photon fluorescent FA probe (Na-FA)

Living HeLa cells, liver slides

7.1 × 10⁻⁷ M

Khataee et al. (2016)

Flow injection chemiluminescence (CL) method

KMnO₄, CdS QDs

Underground water (9.86 ± 1.2 μg/L)

Drinking water (9.52 ± 1.96 μg/L)

0.0003 μg/L and 1.2 μg/L

Yang et al. (2016)

QCM resonator

Graphene oxide

Determined concentrations(3.5 ppm, 2.6 ppm, 1.7 ppm, 0.9 ppm, and 0.5 ppm)

0.06 ppm

Wahed et al. (2016)

HPLC

2,4-dinitrophenylhydrazine

Cereals (10.74 mg/kg); Fish (26.2 mg/kg); Leafy vegetables (5 mg/kg); Non-leafy vegetables (2.5 mg/kg); Fruits (3.08 mg/kg); Milk (3.0 mg/kg)

0.39 mg/L

Backe (2017)

Solid-phase extraction (SPE) and liquid chromatography/tandem mass spectrometry (LC/MS/MS)

Using electrospray ionization

Pharmaceuticals, steroids, pesticides, and personal care products

1.0 ng/L in water

Barkhordari et al. (2017)

Needle trap device (NTD)

Packed with nanoporous silica aerogel

Aqueous and urine samples

0.01–0.03 μg/L (in aqueous sample), 2.8–7.3% (in urine)

Gu et al. (2017)

HPLC-UV

2,4-dinitrophenylhydrazine

Fresh squid contained less than 20 mg/kg, free formaldehyde concentration in shredded squid was 48.5 mg/kg

15 mg/kg

Brewer et al. (2017)

Spectrofluorometry

2-Aza-Cope-based trigger of RFAP-1 and RFAP-2

Live-cell imaging and/or flow cytometry

0.3 μM

Liang et al. (2017)

Fluorometric

Coumarin-hydrazonate-based fluorogenic probe (PFM)

Live neurovascular cells and brain tissue imaging

0.4 μM

Bruemmer et al. (2017)

Fluorometric

2-Aza-Cope-based trigger of FAP

Fluorescence imaging and flow cytometry

10 μM

Brandão et al. (2017)

Gas-diffusion microextraction coupled with spectrophotometry

Acetylacetone (Hantzsch reaction)

Cork agglomerates

0.14 mg/kg

Gong et al. (2017)

HPLC-fluorescence detection

Dansylhydrazine

Packaging paper

19.2 μg/kg

Wongniramaikul et al. (2018)

Colorimetry

Biodegradable colorimetric film

Food

1.413 mg/kg

Zhao et al. (2018)

HPLC silica gel plate

Fluorescent probe (TPE-FA)

Gaseous formaldehyde

0.036 mg/m³

Xu et al. (2018)

Fluorometric

Regeneration fluorescent probes, Naphthalene-Formaldehyde Probe-1 (NAP-FAP-1) and Naphthalene-Formaldehyde Probe-2 (NAP-FAP-2)

Formaldehyde solution and HeLa cells

NAP-FAP-1 0.48 μM and NAP-FAP-2 0.145 μM

Bruemmer et al. (2018)

Fluorometric and chemiluminescence

Chemiluminescent formaldehyde probes 540 and 700 (CFAP540 and CFAP700)

Living cells and mice

–

Temel and Gürkan (2018)

Ultrasound-assisted cloud-point extraction with spectrophotometry

Cationic phenothiazine group dye

Cosmetic products

0.38 μg/L

Sebaei et al. (2018)

HPLC

2,4-Dinitrophenylhydrazine

Dairy products

0.01 mg/kg

Yoshikawa et al. (2018)

HPLC

Methyl acetoacetate derivatization

Water

0.96 μg/L

Miralles et al. (2018)

Reversed-phase dispersive liquid-liquid microextraction (RP-DLLME), liquid chromatography-ultraviolet/visible (LC-UV/Vis)

Pentane-2,4-dione

Cosmetic products

30 ng/g

Brandão et al. (2018)

Gas-diffusion microextraction, spectrofluorometry

Acetylacetone

Cosmetic products

1.98 mg/kg

Liu et al. (2018)

Fluorometric

Polymeric fluorescent probes

Cells or zebrafish

–

Guo et al. (2018)

Smartphone-based microfluidic colorimetric sensor

AHMT

Gaseous formaldehyde

0.01 ppm

Yang et al. (2018)

Fluorometric

2-Aza-cope-based trigger of HT-1、HT-2

Human serum

HT-1 10.4 μM and HT-2 1.36 μM

Akshath and Bhatt (2018)

Supramolecular nano-sniffers

Supramolecular nanoparticle hybrids

Fruit juice and wine

0.001 ng/mL

Liu et al. (2019)

Fluorometric

Ruthenium(II) complex probe, Ru-FA

Formaldehyde solution and biological samples, imaging of endogenous formaldehyde in mice

–

Zhang et al. (2019)

HPLC

Hydrophobic deep eutectic solvents

Biological and indoor air

0.2 μg/L

Fu et al. (2019)

Capillary electrophoresis with laser induced flurescence (LIF) detection

Fluorescent probe N-propyl-4-hydrazino-naphthalimide (NPHNA)

Formaldehyde in single cell

5 Amol

Pinto et al. (2019)

Square-wave voltammetry

Acetylacetone reagent

All mushroom samples, fresh and dried shiitake (Lentinula edodes), and fresh shimeji (Pleurotus ostreatus)

0.13 mg/L

Ogasawara et al. (2019)

HPLC with an UV detector

2,4-dinitrophenylhydrazine (DNPH)

Quality control of the Zika vaccine

0.05 μg/mL

Ji et al. (2019)

Fluorometric

Perylene-based fluorescent nanoprobe

Cells

0.96 μM

Dvořák et al. (2020)

Headspace liquid acceptor system (HLAS), square-wave voltammetry (SWV)

Acetylacetone reagent

Wood-based products

0.57 mg/kg

Zhang et al. (2020)

Fluorescence and luminescent measurements

Activity-based genetically encoded fluorescent and luminescent probes

Aqueous solutions and living mammalian cells

–

Yang et al. (2020a)

Chemiluminescence

Formaldehyde gas sensor based on chemiluminescence on nano-Pt/Mo4V6Ti10O47

Gaseous formaldehyde

0.002 mg/m³

Jiang et al. (2020)

Fluorometric

Hydrazinyl naphthalimide-based Fluorescent probe RBNA

Living cells and zebrafish, seafood

0.21 μM

Dong et al. (2020)

Surface-enhanced Raman spectroscopy coupled with microhydrodistillation

Au nanoparticles and [Ag(NH3)2]+

Beer samples

0.08 mg/L

Yang et al. (2020b)

Fluorometric

CD@SiO₂-NH₂-Ag+ fluorescent probes

Gaseous formaldehyde

3 ppb

Kochetkova et al. (2021)

Spectrofluorometry

Acetylacetone, thymol

Milk

15 μg/L

Teišerskytė et al. (2021)

Biosensing techniques

NAD-dependent formaldehyde dehydrogenase from Pseudomonas sp. (FDH) immobilized on the gold nanoparticle-modified gold electrode

River water

0.05 mM

Rajendar et al. (2021)

Reversed phase HPLC-UV

Acetonitrile

Vaccine products

–

Abe et al. (2021)

LC-MS/MS

2,4-dinitrophenylhydrazine

Bottled mineral water

–

Kumaravel et al. (2021)

Electrochemical techniques

Two ratiometric electrochemical molecular redox probes, formaldehyde oxidative latent probe (FOLP), and dihydroxy-formaldehyde oxidative latent probe (HFOLP)

Live cells, whole blood

FOLP 48.2 nM and HFOLP 31.6 μM

Naksen et al. (2022)

Fluorometric

Fluorescent probes, nitrogen-doped carbon dots (N-CDs)

Food samples

1.5 mg/L

Qiao et al. (2022)

Fluorometric

Fluorescent nanoprobe

Formaldehyde solutions

10 μM

Quan et al. (2022)

Fluorometric

Fluorescent probe, FormAFP

Living cells

66 nM

Zhang et al. (2022)

Fluorometric

Two-photon fluorogenic probe

Living cells

67.2 nM

Liu et al. (2022)

Fluorometric

Cell-permeable fluorescence probe

Living cells

2.7*10⁻⁷ M

Ding et al. (2022)

Fluorometric

Near-Infrared Fluorescence Probe-NHNH(2)

Mice, Zebrafish

0.68 μM

Wang et al. (2022c)

Fluorometric

Two-photon fluorescent agent, 7-Hydrazinyl-4-(trifluoromethyl)-2H-1-benzopyran-2-one (TFCH)

Living cells, living brains of mice

0.11 μM

Tantipanjaporn et al. (2022)

Fluorometric

Quinolizinium-based fluorescent probes, QA1 and QA2

Aqueous solution, serum, and paper format

QA1 5 μM and QA2 1 μM

Kim et al. (2022)

Fluorometric

Rhodamine-based fluorescent probes 1 and 2

Aqueous solutions and cells

Probe1 1.24 μM and probe 2 0.59 μM

Jiang et al. (2022)

Fluorometric

Fluorescent probes based on the mechanism of 2-aza-Cope rearrangement, FA-2

Living cells

0.65 μM

Liang et al. (2023)

Fluorometric

Quinoline based fluorescent probe

Living cells and zebrafish

8.1 nM

Li et al. (2023)

Fluorometric

"Off-on" sensor probe NA-SF

Living cells and plants

–

Schann et al. (2024)

Biosensor

Formaldehyde assimilation enzymes

Cell growth

From 30 μM to 13 mM

Tongdee et al. (2024)

Microwell plate titration

Semi-quantitative analysis

Food

–

De Araújo et al. (2024)

Fluorimetric determination

Immobilized in a flow cell

Aqueous formaldehyde

–

Cadeado et al. (2025)

Fluorescence measurement

Formaldehyde in milk

Food

46–114 μg L⁻¹

2 A Variety of Methods for Analysis of Formaldehyde

The Environmental Protection Agency (EPA) of the United States suggested that the acceptable daily intake (ADI) of formaldehyde is 0.2 mg/kg body weight and warned that formaldehyde exposure higher than ADI may potentially harm health (EPA 1999). Overload of exogenous formaldehyde leads to many health-related problems (Tang et al. 2009), including cognitive impairment (Marceaux et al. 2008) such as learning, memory, and equilibrium and even damage to the brain (Flyvholm and Menne 1992; Perna et al. 2001). Under physiological conditions, learning activity induces a transient generation of hippocampal formaldehyde, which promotes memory formation by enhancing N-methyl-D-aspartate (NMDA)-currents. However, aging leads to formaldehyde accumulation in brain for the dysregulation of formaldehyde metabolism; and excessive formaldehyde directly impairs memory by inhibiting NMDA-receptor (Kou et al. 2022). Furthermore, according to International Agency for Research on Cancer (IARC) (IARC 2004), Formaldehyde is considered as a dangerous human carcinogen. Thus, detection and determination of both exogenous and endogenous formaldehyde are imperative to human health and daily life.

To determine this smallest aldehyde molecule, different methods have been developed for different purposes. Sawicki et al. estimated formaldehyde with colorimetric procedure using 3-methyl-2-benzothiazolone hydrazone (Sawicki et al. 1961). After that, different methods and protocols were established such as ion chromatography (Lorrain et al. 1981), polarography (Septon and Ku 1982), radiometric analysis with dimedone 14C (Szarvas et al. 1986), spectrophotometry with pararosaniline (Pedrero et al. 1989), HPLC (Houlgate et al. 1989), adsorption voltammetry (Chan and Xie 1997), gas chromatography (GC; Ebeler et al. 1997), flow injection analysis (Bechmann 1998), preconcentration-chemical ionization mass spectrometry (Kato et al. 2001), fluorescence (Motyka and Mikuska 2004), interdigitated microelectrode array (Tomcík et al. 2005), gas sensor (Kawamura et al. 2005), polydimethylsiloxane microfluidic chip (Weng et al. 2009), 13C/1H NMR (nuclear magnetic resonance) spectroscopy (Emeis et al. 2010; Monakhova et al. 2013), electro-spinning/netting nano-fiber/nets (Wang et al. 2012a), Pd-functionalized SnO₂ sensor (Tian et al. 2013), differential optical absorption spectroscopy (DOAS) (Li et al. 2014), fluorescent probe (Brewer and Chang 2015; Xu et al. 2016), and flow injection chemiluminescence (Khataee et al. 2016). In the recent decade, more methods have been invented and used than ever before. Different techniques were applied in the analysis of formaldehyde. Backe derivatized formaldehyde into 3,5-diacetyl-1,4-dihydrolutidine (DDL) using an acetylacetone solution (Backe 2017). The method includes a derivatization procedure that is newly adapted to HPLC-MS/MS; therefore, structures were proposed for the product ions of the derivative DDL. Among so many methods, the HPLC is one of the most common approaches employed with different chemical reagents. Adducts between formaldehyde and other reagents can be selectively separated by HPLC and then quantified by an electrochemical approach. A fluorometric method to determine formaldehyde in candle smoke was reported by using HPLC. These studies focused on the analysis of formaldehyde levels in the air, water, and food. Consequently, the World Health Organization (WHO) suggests the 30 min exposure limit of 0.08 ppm (0.107 mg/m³) (2001). The Environmental Protection Agency of the United States suggested that the ADI of formaldehyde is 0.2 mg/kg body weight (EPA 1999).

The determination of concentration of formaldehyde and malondialdehyde (MDA) in 20 rats showed a variation, respectively, of 10.0–900.0 ng/mL for formaldehyde and 18.0–800.0 ng/mL for MDA. Formaldehyde is a well-known environmental toxic hazard. It is also a product of oxidative deamination of methylamine catalyzed by semicarbazide-sensitive amine oxidase (SSAO). Increased SSAO-mediated deamination has been implicated in some pathophysiological conditions, such as diabetic complications. The measurement of formaldehyde in the enzymatic reactions and in vivo production using conventional methods was not straightforward due to limitations of selectivity and sensitivity. A novel high-performance liquid chromatography (HPLC)/electrochemical procedure for the measurement of formaldehyde has been developed. The measurement is based on the formation of adducts between formaldehyde and dopamine. These adducts can be selectively purified and concentrated using a batch method of alumina absorption, separated by HPLC, and electrochemically quantified. The method is highly selective and substantially more sensitive, that is, detection of picomole levels of formaldehyde, than the conventional methods. The procedure not only facilitates the assessment of SSAO activity in vitro but also is useful for assessing formaldehyde in tissues and biological fluid.

In addition, the relationship between formaldehyde and cognitive ability or other requirements can be assessed by determination of formic acid, or combination of formaldehyde and formic acid (Wang et al. 2022a).

3 2,4-Dinitrophenylhydrazine, One of the Most Commonly Used Reagents

In the determination of exogenous and endogenous formaldehyde, different reagents and techniques have been developed. Among the most used reagents, 2,4-dinitrophenylhydrazine (DNPH) is most used with different analytic instruments and techniques including spectrophotometry (Pedrero et al. 1989), GC (Ebeler et al. 1997), gas chromatography-mass spectrometry (GC-MS) (Zhang et al. 2009), ion chromatography (Lorrain et al. 1981), HPLC (Houlgate et al. 1989), and HPLC-MS (Iqbal and Novalin 2009). In 1989, Houlgate et al. used DNPH to analyze the mainstream cigarette smoke (5 ± 0.07 μg per cigarette) with HPLC. Among the different methods, HPLC with ultraviolet detector method is commonly used to monitor aqueous formaldehyde. In this method, sample collected impregnates with DNPH. Formaldehyde can be converted to the DNPH derivative. Then the derivatives were separated by column and detected. The method was approved by the American Society for Testing Materials (ASTM) as a standard test method for determination of formaldehyde.

4 Determination of Brain Formaldehyde

The levels of brain formaldehyde depend upon the analytic methods, that is, different methods produce different values of concentrations of brain formaldehyde. This is reasonable because different methods have different sensitivities to formaldehyde, with different performance schemes. Maboudou et al. determined the rat brain formaldehyde with a GC-MS method. They homogenized rat brains with deionized water and derivatized the extract with DNPH to obtain formaldehyde hydrazine derivatives. The determination of concentration of formaldehyde in 20 rats showed a variation of 0.33–30.00 μM for formaldehyde in the homogenate of the brain (Maboudou et al. 2002). Yu et al. used a high-performance liquid chromatography/electrochemical procedure for measuring formaldehyde. The formaldehyde level of mouse brain tissues was estimated to be 11 μmol/kg tissues (Yu et al. 2003). Tong et al. employed HPLC. As described by Su et al., brain tissues of porcine were homogenized, and the supernatant fractions (weight of tissue: ultrapure water = 1: 4) were analyzed by DNPH coupled with HPLC after centrifugation (3000 rpm, 4 °C, 10 min). The formaldehyde standard curve was made with analytic purified formaldehyde. The concentrations of formaldehyde in parietal lobe, frontal lobe, temporal lobe, occipital lobe, hippocampus, cerebellum, and brain stem of porcine brain (n = 5) were measured. The porcine brain formaldehyde was 75.5–83.4 μmol/kg fresh brain tissues measured by this improved method. Recoveries of spiked formaldehyde at low and high levels were 95.96–102.04% with relative standard deviations (RSDs) less than 10% (Su et al. 2011). Genetically encoded formaldehyde sensors allowed real-time monitoring and spatial–temporal visualization of formaldehyde in mouse brain tissues (Zhu et al. 2021). The first excited-state intramolecular proton transfer (ESIPT)-based probe ABTB, for the highly sensitive and selective imaging of formaldehyde, was successfully applied in monitoring endogenous formaldehyde in the brain of Alzheimer’s disease (AD) mice (Bi et al. 2021). In addition, the formaldehyde level in solid tissues, for instance, teeth, was measured by HPLC-Optimum-performance laminar chromatography (OPLC)-MS. Results showed an increase in formaldehyde level in carietic teeth in comparison to healthy teeth (Rózyło et al. 2000).

5 Analysis of Formaldehyde in Urine and Body Fluid

Szarvas et al. estimated the formaldehyde concentration in human urine and blood with dimedone 14C, a reagent for radiometric analysis (Szarvas et al. 1986). The formaldehyde in blood and urine varied between 0.01–0.02 mM and 0.08–0.13 mM, respectively. GC has been used to compare the concentrations of formaldehyde between the expired air of tumor-bearing mice (1.43–2.98 μM) and control mice (0.77–1.01 μM) (Ebeler et al. 1997). The concentration of urine formaldehyde from healthy individuals ranges from 1.89 to 4.81 μM, as determined by Takigawa et al. using gas chromatography (Takigawa et al. 2007). Using selected-ion flow-tube mass spectrometry (SIFT-MS), the mean concentrations of urine formaldehyde in patients with prostate cancer and bladder cancer were shown to be 0.83 μM and 2.83 μM, respectively, compared with 0.37 μM in healthy controls (Spanel et al. 1999). Preconcentration of the body fluid samples rendered formaldehyde more detectable by SIFT-MS. Formaldehyde concentrations in HeLa-S3 cervical cancer, K562 leukemia, and MCF-7 breast cancer cell lines range from 1.5 to 4.0 μM (Kato et al. 2001). The use of HPLC combined with an electrochemical procedure is an established method for the measurement of formaldehyde in vivo (Su et al. 2011). Using this method, the concentration of rabbit urine formaldehyde is about 18 nM and that of mouse liver, kidney, and brain tissues are 63, 51, and 11 nmol/g tissue, respectively (Yu et al. 2003). Another method to determine formaldehyde in blood samples by HPLC utilizes a fluorescence assay. Derivatization of human plasma with ampicillin leads to a fluorescent adduct that can be measured with a fluorescence spectrophotometer. The average level of human blood formaldehyde as determined by Fluo-HPLC is approximately 40 μM (Luo et al. 2001). Thin-layer chromatography is used to estimate changes in the levels of formaldehyde in methylation and demethylation (Kalász 2003). Yu et al. reported that the rabbit urine samples were spiked with 0.25 nM formaldehyde and subjected to extraction with alumina and HPLC assessment (Yu et al. 2003). Urine-based formaldehyde has been reported to be a potential biomarker for AD, and the results revealed formaldehyde significantly increased (Wang et al. 2022b). In addition, the cerebrospinal fluid (CSF) levels of Aβ₄₀, Aβ₄₂, and formaldehyde were measured in 56 rhesus monkeys of different ages, ranging from 4 to 26 years old. Results revealed significant declines in Aβ₄₀ and Aβ₄₂, and an increase in formaldehyde with age (Li et al. 2020). Among those methods to analyze urine formaldehyde, Su et al. preferred the method of HPLC coupled with DNPH in the clinical determination of uric samples because it is sensitive and repeatable, and described as follows (Su et al. 2011).

6 An Example for Analysis of Urine Formaldehyde Using HPLC Coupled with DNPH Absorbance

Yu et al. analyzed urine formaldehyde using HPLC coupled with DNPH absorbance and performed neuropsychological tests for aged people from the communities of Beijing city in a double-blinded manner (Yu et al. 2014a). Also, they measured concentrations of urine formaldehyde for AD patients compared with the age-matched participants. The average concentration of urine formaldehyde in AD patients is significantly higher than that of the controls (Li et al. 2016). Qiang et al. also employed the method in the determination of formaldehyde levels in mouse brain, kidney, liver tissues, and the medium of cells (Qiang et al. 2014). The microbiota–gut–brain axis is regarded as the human “second brain,” which is involved in neurodegenerative diseases such as AD, vascular dementia, and Parkinson’s disease (Hu et al. 2016). Liu et al. found a marked increase of formaldehyde in cecum digestion contents of APP/PS1 transgenic mouse compared with C57BL/6J wild-type mouse (Liu et al. 2017).

Ten milliliters of urine were collected from each participant and immediately placed on ice or stored at −70 °C. To prevent the samples from repeated thaw-frozen cycles, the urine should be analyzed freshly or stored in aliquots. The urine sample (1 mL, thawed at 4 °C) was pipetted into a 1.5 mL Eppendorf tube and centrifuged (12,000 rpm for 10 min at 4 °C). A 0.4 mL aliquot of the supernatant was mixed with DNPH, final concentration 0.1 g/L in acetonitrile, and 0.1 mL trichloroacetic acid. Samples were vortexed vigorously for 30 s and then centrifuged (12,000 rpm for 10 min at 4 °C). The supernatant was added to a 2 mL glass vial, heated in a 60 °C water bath for 30 min, and then analyzed by HPLC. The mobile phase was 65% acetonitrile water solution. The flow rate was 0.8 mL/min and column temperature 35 °C. The formaldehyde-DNPH derivative was eluted from the HPLC column at a retention time of 6–7 min at the maximum wavelength of 355 nm as previously described (Su et al. 2011).

Urine formaldehyde was also determined with HPLC coupled with fluorescence (ampicillin) detection as described (Luo et al. 2001). Using this method, the concentrations of urine formaldehyde of age-matched control, mild cognitive impairment (MCI), moderate cognitive impairment, and server cognitive impairment were determined as 0.083 ± 0.001 mM, 0.196 ± 0.69 mM, 0.293 ± 0.050 mM, and 0.313 ± 0.046 mM, respectively (Tong et al. 2011). These values are significantly higher than those determined by HPLC coupled with DNPH, which generates the urine formaldehyde of AD patients as 13.70 ± 5.17 (n = 62) and that of age-matched participants as 9.61 ± 2.90 (n = 69). The HPLC with fluorescent ampicillin is more sensitive, but fluorescence is susceptible to interference, such as changes in temperature, acidity of solution, and concentrations of samples.

It should be noticed that formaldehyde has the capacity to react with proteins and produce modified derivatives. Thus, the accurate determination of blood formaldehyde is difficult since blood is rich in proteins. Formaldehyde is prone to react with serum proteins. On the other hand, determination of human urine formaldehyde by HPLC coupled with DNPH is precise, convincible, and reproducible because urine contains much less proteins. Therefore, in clinical trials or epidemiological investigations, we would like to suggest the concentration values of urine formaldehyde should be more convincible.

7 Development of Methods with Nano-techniques

Nowadays, significant attention has been brought to the development of sensitive, specific, cheap, and reliable sensors for real-time formaldehyde monitoring. Several relatively low-cost and convenient methods without derivation or chromatography were developed, because the operation of derivation, elution, and extraction needs lots of time or money. Among various techniques, quartz crystal microbalance (QCM) (Yang and He 2016) could measure nanogram-scale changes in mass on the quartz crystal surface based on the Sauerbrey equation by recording its frequency shifts. QCM with graphene oxide (GO) sensors showed high sensitivity, good reversibility and repeatability, and good selectivity to formaldehyde. GO-functionalized QCM resonators respond to formaldehyde in 60 s and are stable in the sensing characteristics at least up to 100 days.

Recently, a rapid and simple formaldehyde determination technique with a microfluidic chip was developed (Weng et al. 2009). This technique is based on the reaction between formaldehyde and acetylacetone in the presence of ammonium acetate to form yellow DDL, which has a differential absorbability of around 410 nm violet light. Microfluidic device was designed to decrease the sample volume and to make multiple sample detection. Compared with the conventional formaldehyde detection system, the microfluidic chip method can realize rapid detection within 1 min, use a small sample volume about 1–2 μL, and reduce the cost significantly. As described by Tang et al., molecular imprinting technology is a versatile and promising technology for practical applications in many areas, particularly chemical sensors (Tang et al. 2017). They presented a titanium dioxide nanotube array (TiO₂-NTA) for increasing its surface-to-volume ratio in a chemical sensor for detecting formaldehyde, a toxic common indoor pollutant gas.

Quantum dots-Gold nanoparticle (QDs-GNP)-based fluorescence resonance energy transfer (FRET) probes were applied for enzyme-operated biosensors that can specifically turn-on fluorescence induced by co-factor or product formed from enzymic reaction. This phenomenon was applied for the successful detection of formaldehyde using Nicotinamide adenine dinucleotide (NAD⁺)-dependent formaldehyde dehydrogenase. The study proposed nano-sniffer could successfully detect formaldehyde from 0.001 to 100,000 ng/mL (R² = 0.9339) by the turn-off–turn-on principle (Akshath and Bhatt 2018). A novel formaldehyde gas sensor based on chemiluminescence on nano-Pt/Mo₄V₆Ti₁₀O₄₇ was reported to detect 0.002 mg/m³ formaldehyde (Yang et al. 2020a). The reaction of formaldehyde with the solution containing Au nanoparticles and [Ag(NH₃)₂]⁺ through Tollens’ reaction is described to form Au@Ag nanoparticles (Au@AgNPs) and rapidly determinate the formaldehyde residues by surface-enhanced Raman spectroscopy coupled with microhydrodistillation (Dong et al. 2020).

8 Fluorescent Probe to Detect Formaldehyde in Living Cells

Methods for monitoring formaldehyde in living biological specimens are important to investigate the elevations of formaldehyde implicated in a variety of disease pathologies, such as neurodegenerative diseases and age-related cognitive impairment. Traditional methods for biological formaldehyde detection rely on sample destruction and/or extensive processing, resulting in a loss of spatiotemporal information. Therefore, specific probes for formaldehyde in cellular activity, especially kinetic study of formaldehyde in living cells, are urgently required.

As an efficient tool for formaldehyde detection, fluorescent probes exhibit the advantages of low cost, ease of use, facile operation, etc. Not a few methods of high selective detection of endogenous formaldehyde in living cell were exploited. Formaldehyde reacts with 2-aza-Cope in order to transform a homoallylic amine into an aldehyde coupled with a fluorogenic turn-on response (Brewer and Chang 2015). Formaldehyde probe-1 (FAP-1) is capable of detecting exogenous and endogenous formaldehyde in living cells. Using confocal microscopy, the images were taken 30 min after addition of FAP-1. The in vitro detection limit for formaldehyde was 5 μM. Another method detected the level of formaldehyde in HeLa cells by naphthalene-based fluorescent probe (AENO) (Xu et al. 2016). This probe AENO can quantitatively detect formaldehyde with a detection limit of 0.57 μM, being essentially insensitive to pH ranging from 5.5 to 10.5. The fluorescence after incubation with AENO was linearly correlated with formaldehyde ranging from 0 to 1000 μM, and the endogenous formaldehyde in HeLa cells was calculated to be 209 μM. As reported by Tang et al., a new organelle-targeted fluorescent formaldehyde probe (Na-FA-Lyso) was developed to detect the endogenous formaldehyde in the lysosomes in living cells (Tang et al. 2016a; Tang et al. 2016b). The new probe Na-FA-Lyso was suppressed in its photoinduced electron transfer (PET) pathway and turned on after reacting with formaldehyde. The detection limit of the probe was calculated to be 5.02 μM. Yue et al. detected formaldehyde in brain tissues by using Fluoral P (Yue et al. 2017). Those powerful molecular probes improve the investigation of physiological and pathological roles of endogenous formaldehyde on the cellular and subcellular level.

To help fill up this technological gap, Brewer and Chang have designed, synthesized, and biologically evaluated a fluorescent probe for live-cell formaldehyde imaging that relies on a formaldehyde-induced aza-Cope rearrangement. A method exploited an formaldehyde-induced 2-aza-Cope reaction to transform a homoallylic amine into an aldehyde coupled with a fluorogenic turn-on response (Brewer and Chang 2015). FAP-1 is capable of detecting exogenous and endogenous formaldehyde in living cells. Using confocal microscopy, the images were taken 30 min after addition of FAP-1. The in vitro detection limit for formaldehyde was found to be 5 μM (Grömping and Cammann 1993). Liang et al. developed a coumarin-hydrazonate-based fluorogenic probe (PFM) based on a finely tailored stereoelectronic effect, which could track endogenous formaldehyde in live neurovascular cells with excellent temporal and spatial resolution; the limits of detection of formaldehyde is 0.4 μM (Liang et al. 2017). Two formaldehyde regeneration fluorescent probes (NAP-FAP-1, and NAP-FAP-2) were also produced. An unprecedented regiospecific formaldehyde-induced intramolecularity strategy is implemented in the probe design, which adopts 3-(benzylamino)-succinimide as the formaldehyde-selective reaction group NAP-FAP-1 is highly sensitive with detection limit of 0.48 μM and NAP-FAP-2 has similar selectivity with detection limit of 0.145 μM (Xu et al. 2018). These fluorescent probes are expected to be developed into a convinced, convenient, and highly effective method in determination of both exogenous and endogenous formaldehyde.

Abnormally high level of formaldehyde induced the cellular oxidative stress (Evans et al. 2016), resulting in abnormal modification and accumulation of protein, neuron death, and cognitive impairment (Xiong and Zhu 2016; He 2017). To investigate the relation of oxidative stress and excess formaldehyde, which leads to neuron death and cognitive dysfunction, the technique for monitoring the dynamic distribution of formaldehyde in living cell has been performed by Chen et al. (2017). In the cellular experiment, they added H₂O₂ to bEed.3 cells and found that the yield of formaldehyde is localized in the lysosome detected by the formaldehyde molecular probe (Fig. 17.1). They added formaldehyde to the cells and also observed that the signal of formaldehyde markedly increases inside lysosome and then decreases with time. Furthermore, they isolated lysosomes from rat brain and demonstrated the location of formaldehyde in the lysosome (Chen et al. 2017). Biomedical investigations revealed that excessive formaldehyde generation is possibly a critical factor for tissue cancerization, cancer progression, and metastasis. A novel “dual-key-and-lock” strategy-based ruthenium(II) complex probe, Ru-FA, is reported as an effective tool for formaldehyde detection in vitro and in vivo; luminescence imaging of lysosomal formaldehyde in live cells, visualization of tumor-derived endogenous formaldehyde, and monitoring of formaldehyde scavenging in mice were achieved, followed by the successful demonstration on detection of formaldehyde in tumors and other organs (Liu et al. 2019).

Fig. 17.1

Fluorescence image of the endogenous formaldehyde in the bEed.3 cells. Fluorescence image of FAP-1 (red, panel a); fluorescence image of Lyso Tracker Green DND-26 (green, panel b); merged image of panel a and panel b (panel c); fluorescence image of FAP-1 (red, panel d); fluorescence image of Mito Tracker Green FM (green, panel e); merged image of panel d and panel e (panel f); bright-field image of the cells as control (panel g); bright-field image of the cells treated with PAP-1 (panel h); bright-field image of the cells treated with PAP-1 and 0.1 mM formaldehyde (panel i). Scale bar: 10 μm. (Source: Chen et al. 2017)

9 Genetically Encoded Fluorescent and Luminescent Probes for Detecting Formaldehyde in Living Cells

Recently, an formaldehyde-reactive lysine analogue, PrAK, was site-specifically incorporated into the essential lysine sites of enhanced green fluorescent protein (EGFP) and firefly luciferase (fLuc) to afford fluorescent and luminescent formaldehyde probes, respectively. The activity-based genetically encoded fluorescent and luminescent probes are capable of visualizing formaldehyde at physiologically relevant levels in living mammalian cells by fluorescence and luminescence imaging (Zhang et al. 2020). Zhu adopted a structure-based study of the underlying mechanism of the formaldehyde-responsive transcription factor HxlR from Bacillus subtilis, which showed that HxlR recognizes formaldehyde through an intra-helical cysteine-lysine crosslinking reaction at its N-terminal helix α1, leading to conformational change and transcriptional activation. Leveraging this formaldehyde-induced intra-helical crosslinking and gain-of-function reorganization, allowed spatial–temporal visualization of formaldehyde in mammalian cells and mouse brain tissues (Zhu et al. 2021).

10 Conclusion

In recent years, formaldehyde is not only studied as an important exogenous carcinogenic substance but also as one of the endogenous reactive carbonyl species produced by enzymatic oxidation of the amino acids, lipids, and carbohydrates, as well as by demethylation. Methods for monitoring formaldehyde in living biological specimens are important to investigate the elevations of formaldehyde that implicates a variety of disease pathologies, such as cognitive impairment, neurodegenerative diseases, heart disorders, cancers, diabetes, and chronic hepatitis. Barkhordari et al. designed a NTD packed with nanoporous silica aerogel as a sorbent and used as a new technique for sampling and analysis of formaldehyde and acrolein in urine. The ranges of detection limit, quantification limit, and relative standard deviation (RSD) were 0.01–0.03 μg/L, 0.03–0.1 μg/L, and 2.8–7.3%, respectively. They believed that the technique can be applied as an effective and reliable method for sampling and analysis of aldehyde compounds from different biological matrices such as urine and exhalation (Barkhordari et al. 2017). Ultraperformance liquid chromatography tandem mass spectrometry was used to determine formaldehyde hemoglobin adducts in humans as a biomarker for formaldehyde exposure (Yang et al. 2017). A miniaturized sensor has been developed for detection of formaldehyde fumes (Zilberstein et al. 2017). The signal response has been assessed over low (20–120 ppb) as well as higher (1–15 ppm range) levels. A reagentless amperometric formaldehyde-selective chemosensor was established by Demkiv et al. based on platinized gold electrodes (Demkiv et al. 2017). The determination of formaldehyde in liquid biological samples in cells and organisms is useful and important. As the technique advances in recent years, current efforts are underway to develop more straightforward detection methods with greater sensitivity, lower cost, and improved portability. Among them, reaction-based fluorescent and chemiluminescent probes for formaldehyde detection and imaging are well developing, which offers powerful tools to discover the diverse functions of formaldehyde in physiology and pathology processes (Huang et al. 2022). It is expected that many convenient and robust tools will be used for better understanding to explore formaldehyde biology.

Acknowledgments

All the grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025

R. He (ed.)Formaldehyde and Cognitionhttps://doi.org/10.1007/978-981-96-7281-3_18

18. Potential Drug Interventions on Formaldehyde-Induced Neuronal Toxicity

Zijian Zhang¹, Qian Hua² and Rongqiao He3  

(1)

Department of Medicine, Baylor College of Medicine, Houston, TX, USA

(2)

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China

(3)

State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Psychology, Chinese Academy of Sciences, Beijing, China

Rongqiao He

Email: herq@ibp.ac.cn

Abstract

Over one hundred years, a great deal of research has been focused on the clinical phase of dementia, and on single-target drugs to intervene the progression of Alzheimer’s disease (AD). However, a groundbreaking advancement in the treatment still needs to be made to stave off AD. So far, many drugs and methods have been tried to treat and intervene AD in basic research and clinical trials. In order to reduce the onset and progression of age-related cognitive impairment, different interventions have been studied and applied in Alzheimer’s disease treatments, such as developing multiple targeting drugs, ameliorating lifestyle, regulating diet, providing music care, attending physical exercises, and participating in social activities. The multidomain intervention will be one of the comprehensive therapies for Alzheimer’s disease patients, especially for those in preclinical phases. Therefore, we would like to emphasize that intervention of Alzheimer’s disease needs personalized intervention and medicine, including individualized diagnosis and treatment. Currently, clarifying early pathological changes of preclinical stage is imperative to understand AD. Early diagnosis and intervention could have better effective treatment results. First, we can identify whether the dementia patients suffer from high levels of endogenous formaldehyde and formic acid. Then we may treat them with some Chinese herbs as suggested in this chapter. Improving the brain microcirculation may be worth recommending for intervention of age-related cognitive impairment resulting from aldehyde dysmetabolism. We would like to recommend the integration of Western medicine and traditional Chinese medicine (TCM); for instance, performing the Western diagnosis coupled with the TCM treatment to make the personalized treatment plan for individual patients although the direct relation between so called etiological factors and age-related cognitive impairment is still waiting to be clarified.

Keywords

FormaldehydeTraditional Chinese medicineInterventionNeurotoxicityNeuroprotection

Abbreviations

A

AD

Alzheimer’s disease

ALA

α-Linolenic acid

APOE

Apolipoprotein E

B

BDNF

Brain-derived neurotropic factor

C

CaMKII

Calmodulin-dependent protein kinase II

CAPE

Caffeic acid phenethyl ester

CAT

Catalase

CBS

Cystathionine beta-synthase

CIG

Cornel iridoid glycoside

CNS

Central nervous system

D

DHA

Docosahexaenoic acid

DPCs

DNA–protein cross-links

E

EPA

Eicosapentaenoic acid

ER

Endoplasmic reticulum

ERCC1

Excision Repair Cross-Complementation Group 1

F

FA

Formaldehyde

fMRI

Functional magnetic resonance imaging

G

GSH-Px

Glutathione peroxidase

GSK-3β

Glycogen synthase kinase-3β

H

H₂S

Hydrogen sulfide

I

ICR

Institute for Cancer Research

M

MCI

mild cognitive impairment

MDA

Malondialdehyde

L

LK

Lumbrokinase

N

NAC

N-acetyl cysteine

N2a

Neuro-2a

NBP

DL-3-n-Butylphthalide

P

PI3K

Phosphatidylinositol-3 kinase

PP2A

Proteinphosphatase-2A

PRP

Poria cum radix pini

R

RAT

Rhizoma acori tatarinowii

Res

Resveratrol

ROS

Reactive oxygen species

RP

Radix polygalae

RPA1

Replication Protein A1

RPA2

Replication Protein A2

S

SOD

Superoxide dismutase

T

TCM

Traditional Chinese medicine

TSG

2,3,5,4’-Tetrahydroxystilbene-2-O-β-D-glucoside

V

Vitamin

E

X

XPA

Xeroderma pigmentosum complementation group A

XPC

Xeroderma pigmentosum complementation group C

1 Introduction

The world’s population is aging rapidly. By the year 2050, the group aged 60 and over is expected to achieve 22% of the world population, and there will be approximate 434 million people in the age of 80 and above worldwide estimated by World Health Organization. Unfortunately, more than 20% of people aged 60 and over suffer from neurological or cognitive disorders, among which dementia and depression are the most commonly diagnosed according to the 2015 world report on mental health and older adults. Alzheimer’s disease (AD) contributes 70% of the dementia cases and has been extensively studied. Including AD, those age-related neuronal disorders usually occur with unknown causes and are incurable, age-related, and featured by progressive degeneration of central or peripheral nervous systems and/or death of nerve cells (Gao and Hong 2008).

In recent years, the effect of formaldehyde (FA) on human brain and cognition has attracted more and more attention. It is one of the major pollutants in indoor air and also widely used in some working conditions. So, everyone is living around the formaldehyde. The acute or chronic exposure of FA can cause discomfort and even severe damage to tissue and organs, such as eyes, upper and lower respiratory tract, skin, and central nervous system (CNS). In addition, FA is also produced by the body’s physiological metabolic process and maintained in a state of equilibrium. In recent years, the effects of formaldehyde on the human brain and cognition have garnered growing attention. As people age, formaldehyde accumulates in neurons and other types of brain cells and FA-induced chronic impairments are involved in the development of senile dementia. FA concentration was found to increase with age, and its concentration in AD patients’ urine, cerebrospinal fluid (CSF), and brain tissue was considerably greater than that of age-matched controls. A study revealed that the level of formaldehyde in the urine of APOE ε4 carrier was higher than that of APOE ε4 non-carrier in both healthy individuals and AD patients (Wang et al. 2022). Decreased levels of soluble amyloid beta (Aβ) in the cerebrospinal fluid generally suggest deposition of soluble Aβ in the brain and the formation of senile plaques. Age-related decreases in Aβ 40 and Aβ 42 were accompanied by an increase in FA in a model of rhesus monkeys, who are valuable research animals for neurodegenerative diseases study (Li et al. 2020a, b). Fei et al. highlighted that oxidative demethylation at serine 8/26 site of Aβ could induce FA production, and, in addition, Aβ dampens the activity of formaldehyde dehydrogenase (FDH), the enzyme that degrades FA, leading to FA accumulation. In turn, overload of FA provokes Aβ aggregation in vitro and in vivo by increasing the formation of Aβ oligomers and fibrils. More importantly, degradation of FA by scavenger-NaHSO₃ or coenzyme Q10 improves Aβ neurotoxicity and Alzheimer-related phenotypes in APP/PS1 mice, providing insight that FA might be a potential target for AD therapy (Fei et al. 2021). Given the daily exposure and endogenous production, it is essential to take action to offset the adverse influence of FA on the CNS. In this chapter, protective strategies for cognitive dysfunction induced by FA are discussed. These studies, although they may be still in the experimental stage, can enlighten us to keep us healthy.

Formaldehyde is not just an environmental pollutant but also frequent component of indoor air. Everyone is potentially exposed to formaldehyde at all time, and in certain occupational settings, the amounts are even higher. The detriments of formaldehyde exposure are extensive, especially for those who live or work in such conditions for extended periods of time, and they are not restricted to the central nervous system. Various guidelines, regulations, and references have been issued by different organizations and institutions, including World Health Organization, Centers for Disease Control and Prevention, and Environmental Protection Agency, in each state or country, all of which are easily accessible online. Unfortunately, there are no approved medications for preventing damage caused by exposure to FA.

Because of the complex etiology of AD and the countless risk factors associated with it, traditional Chinese medicine (TCM) with multi-target and multi-session therapeutic features has advantages over single-target therapy. Therefore, in this article we will discuss some of the ways in which TCM treats AD by affecting formaldehyde metabolic disorders. For decades, TCM medications, including formula such as Smart Soup (Hou et al. 2014), Shenwu Capsule (Li and Zhang 2012), Bushen Capsule (Zhang et al. 2015), as well as single herb extracts such as Geniposide (Sun et al. 2013), Resveratrol (Res) (He et al. 2016), Icariin (Song et al. 2015), and DL-3-butylphthalide (Hou et al. 2009), have been researched and developed for AD treatment. They exhibit anti-AD activity through multiple targets and pathways, particularly exerting neuroprotective and neurotrophic/regenerative effects, as well as preserving mitochondria and synapses. They could act on the complex pathogenesis of AD at multi-targets and multi-pathways, especially have both neuroprotective and neurotrophic/regenerative effects, and protect mitochondria and synapses. Thus, these drugs have distinct features and advantages for the treatment of AD. In this chapter, chemicals or compounds that have neuroprotective effect are discussed, including some Chinese medicine herbs, compounds, potential physical methods, and lifestyle interventions. Some of them are related with the dysmetabolism of formaldehyde. So far in clinics, Donepezil and Rivastigmine are usually used for the AD patients with moderate cognitive impairment, and Memantine hydrochloride is for the severe AD patients. Since no report has been released to clarify the relation between these drugs and metabolism of endogenous formaldehyde, we would not discuss them here.

2 Traditional Chinese Medicine

TCM has a storied, millennia-long history. It follows a holistic perspective to comprehend human physiology and pathology. Herbal medicine, acupuncture, massage, exercise, and dietary intervention are all forms of TCM therapy. Hundreds of herbs derived from plants, animals, and minerals comprise the majority of therapies in TCM. A variety of prescriptions or formula based on essential theory of TCM have been recorded. With the modernization of TCM, many chemicals or compounds with broad biological activities have been isolated and purified from herbal medicine. There are a few instances when compounds derived from Chinese herbs have been used to mitigate formaldehyde-induced neuronal cell damage.

As shown in Table 18.1, based on clinical evidence in Chinese medicine, age-related cognitive impairment can be classified into five syndromes—the kidney–marrow deficiency, the Qi deficiency and blood stasis, the phlegm obstructing intelligence, the Yu fire disturbing, and the spleen-Yang impaired by damp—with the goal of establishing the individualized diagnosis and treatment for different AD patients (He 2016). Today numerous extracted and purified potent natural compounds exist on the global pharmaceutical market. Here, we propose extracting useful compounds not only from raw material (plants), but also from decocted formula, since a huge number of new compounds could be generated and formed during decoction. One good example of this is Smart Soup, a traditional Chinese medicine mixture including three TCM herbs that can relieve amyloid pathology and concomitant cognitive deficiencies, despite the fact that none of the three herbs individually shows ameliorative activity.

Table 18.1

The syndromes involved in dementia

Syndrome

Characteristics

References

The kidney-marrow deficiency

Memory loss complicated with tinnitus, hearing loss, decline of language competence, etc., which could be related to more AD patients with a high ratio of apoE4/E4.

Guo (2011)

The qi deficiency and blood stasis

Memory loss complicated with mental fatigue, changes in personality, motive ability decline, hypodynamic behavior, etc., including vascular dementia.

Yuan et al. (1994)

The phlegm obstructing intelligence

Complicated with depression, dizziness headache, less words, abdominal distension, phlegm spitting saliva, burnout trapped heavy, etc.

Zhu (2010)

The stagnated fire agitating the heart

Memory loss accompanied with mania, irritability, words and deeds without thinking, and disorders of life rhythm, etc.

Chen (2007)

The spleen-yang impaired by dampness

Memory loss complicated with dysfunction of enteric nervous system, etc.

Wang et al. (1998)

2.1 Smart Soup

Smart Soup is an ancient Chinese prescription for patients with age-related cognitive decline and has been used in clinical practice for centuries. Smart Soup is composed of three herbs: Rhizoma acori tatarinowii (RAT), which possesses neuroprotective property and could attenuate learning and memory deficits (Lee et al. 2003); Poria cum radix pini (PRP), which has sedative activity (Tong et al. 2010); and Radix polygalae (RP), which could rescue memory and behavioral impairment (Chen et al. 2004; Lee et al. 2009; Shin et al. 2009) as well as has neuroprotective effects (Park et al. 2002; Lin et al. 2012). Each of these three herbs is frequently employed in diverse TCM formula due to their pharmacological effects on central nervous system. Hou et al. have assessed the efficacy of Smart Soup on AD. They demonstrated that oral administration of Smart Soup ameliorates cognitive impairment of AD transgenic mice, which is accompanied with reduced Aβ levels, delayed Aβ amyloidosis, and reduced Aβ-induced gliosis and neuronal loss in the brains. Mechanistic analysis concluded that RP reduces Aβ generation, whereas RAT and PRP exert neuroprotective effects against Aβ (Hou et al. 2014). Their work provides a practical therapeutic strategy against age-related cognitive impairment, for instance Smart Soup formulated by different efficacy drugs.

2.2 Shenwu Capsule

The preparation of Shenwu capsule is distinct from traditional Chinese decoction. It is developed by using a new approach based on the theory of Chinese medicine. The capsule contains extracts of 6 herbs, Polygoni multiflori radix praeparata, Epimedii folium, Ginseng radix et rhizoma rubra, Acori tatarinowii rhizoma, Puerariae lobatae radix, and Ligusticum chuanxiong hort, which are selected from more than 60 classical prescriptions and have been validated in long-term clinic practice. The capsule aims at tonifying the kidney and strengthening the spleen, resolving phlegm and eliminating stasis. Studies have shown that Shenwu capsule can improve learning and memory in a variety of animal models, including APPV717I transgenic mice, Aβ-induced hippocampus injury rats, cholinergic damage-induced AD rats, mitochondrial deficiency-induced AD rats, D-galactose-induced aging mice, cerebral ischemia-induced dementia rats, and diabetes-induced dementia rats (Li and Zhang 2012). Moreover, the clinical trials of Shenwu capsule in China confirmed that it also adequately improves cognitive impairment in patients with mild to moderate AD (Zhong et al. 2007). This may be attributed to the benefits of herbal multi-targeting.

2.3 Bushen Capsule

Bushen capsule is another example of classic TCM prescription that works by nourishing kidney and enhancing brain. It consists of two primary herbs, Alismatis rhizoma and Cistanches herba. Cistanches has neuroprotective benefits in patients with mild cognitive impairment (MCI) or in animal models. Recently, the effect of Bushen capsule on episodic memory in MCI patient was asserted. Episodic memory loss is an important characteristic of early AD symptoms and is considered to be one of the core diagnosis criterions. Neuropsychological tests and functional magnetic resonance imaging (fMRI) examinations showed that Bushen capsule can relieve episodic memory impairment, which is related to the activation or deactivation of temporal lobe and the putamen (Zhang et al. 2015). This finding not only offers us an fMRI-based early diagnosis marker but also puts forward to a feasible preventative medicine.

2.4 DL-3-Butylphthalide

DL-3-n-Butylphthalide (NBP), initially isolated as a pure component from seeds of Apium graveolens in 1978 by the researchers of Institute of Medicine of Chinese Academy of Medical Sciences, is utilized as an antihypertensive herbal medicine for stroke patients. DL-NBP was synthesized subsequently (Fig. 18.1), and was approved by the State Food and Drug Administration of China for clinical use in stroke patients in 2002. Peng et al. suggested that NBP has strong therapeutic premise for the treatment of vascular dementia (VaD) caused by decreased cerebral blood flow (Peng et al. 2007). In 2009, Hou et al. initiated research into the effects and mechanisms of DL-3-butylphthalide on VaD. They recruited 72 VaD patients with MCI. Afte DL-3-butylphthalide administration for 8 weeks, participants’ cognitive scores in Mini-Mental State Examination, activity of daily living scale, and clinical dementia rating were significantly elevated (Hou et al. 2009). Besides, serum concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) decreased. Their data provide a rationale for the use of DL-3-butylphthalide in the treatment of VaD and suggest that antioxidant effects are the mechanism of efficacy of DL-3-butylphthalide. Jia et al. studied the effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease. After 6 months of treatment, their finding further demonstrated that NBP can effectively improve cognition and overall function in the recruited patients (Jia et al. 2016). Recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds allow for the prospect of their clinical implementation in the management of various neurological conditions (Abdoulaye and Guo 2016).

Fig. 18.1

The structure of DL-3-butylphthalide

2.5 Epimedium

Epimedium (Yin yang huo, Fig. 18.2a) is a genus of flowering plants in the family Berberidaceae. It is used to improve liver, kidney, bone, and the cardiovascular system functioning. Icariin (Fig. 18.2b) is an active component of Epimedium. It displays a broad spectrum of pharmacological activity, including inhibition of phosphodiesterase type 5, and augmentation of nitric oxide production and testosterone-like effects, which explains its application in the treatment of erectile dysfunction and impotence (Li et al. 2015). It is also a weak antioxidant with neuroprotective and antidepressant effects (Shindel et al. 2010). The combination of icariin and Panax notoginseng saponins could improve learning and memory deficit and reduce blood viscosity by shielding neurons from oxidative stress in ischemic-reperfusion brain (Zheng et al. 2008).

Fig. 18.2

The traditional Chinese herbs and its active compound to protect against formaldehyde-induced neuronal damage. The herbs are listed on the right column and ingredients on the left. (a) Epimedium; (b) Icariin, the major active chemical of Epimedium. (c) and (d) are the fruit of gardenia and geniposide, respectively. (e) and (f) are turmeric and curcumin. (g) and (h) are Huzhang and Resveratrol

Song et al. found that formaldehyde can induce apoptosis of SH-SY5Y, a human neuroblastoma cell line. Icariin attenuates formaldehyde-induced cell death and decreases Tau phosphorylation through inhibition of glycogen synthase kinase (GSK-3β) (Song et al. 2015). Since Tau protein hyperphosphorylation is one of the most important pathologies of AD, icariin is a promising candidate agent to antagonize formaldehyde-induced learning and memory loss.

2.6 Geniposide

Another important compound for AD treatment from Chinese herbs is geniposide. It is isolated from gardenia fruit extract (Fig. 18.2c) and serves as its main active component. Geniposide (Fig. 18.2d) holds a vast array of biological activities, including antioxidant, anti-inflammatory, antithrombotic, and neuroprotective properties (Suzuki et al. 2001; Yin et al. 2010; Song et al. 2014; Lv et al. 2015). It is considered as a novel approach for the treatment of AD due to its multi-molecular mechanisms that protect the brain from pathological damage (Liu et al. 2015; Zhang et al. 2016).

Recently, it was confirmed that geniposide also protects against formaldehyde-induced neuronal cell death. Formaldehyde at 0.12 mM causes SH-SY5Y cell apoptosis and morphological abnormalities while geniposide can restore these effects by regulating the expression of Bcl-2, p53, caspase 3, and caspase 9 and by boosting the activities of superoxide dismutase and glutathione (Sun et al. 2013). In another neuronal cell line Neuro-2a (N2a), geniposide can also prevent formaldehyde-induced apoptosis and regulate aberrant expression of related genes Akt, Bcl-2, FOXO3, and p53 (Sun et al. 2013; Chen et al. 2014). The combined application of geniposide and ginsenoside, also known as TongLuoJiuNao, has superior efficacy in the treatment of ischemic cerebral stroke and dementia (Chinese SFDA: 2004L01620).

2.7 Curcuminoids

Several curcuminoids could be purified from turmeric (Fig. 18.2e). Curcumin (Fig. 18.2f) is generally considered as most active component and is a robust antioxidant. Its potential to prevent and treat cancer, inflammation, dementia, and other diseases has attracted considerable scientific interest (Sharma et al. 2005). In fact, compelling evidence has proven that formaldehyde could also induce genotoxicity. Formaldehyde exposure caused DNA–protein cross-links (DPCs), and could significantly increase MDA levels, and decreased SOD and glutathione peroxidase (GSH-Px) activity. In addition, the activation of NF-κB and AP-1 could also be induced by formaldehyde treatment. Pretreatment with curcumin ameliorated the formation of DPCs and meantime counteracted formaldehyde-induced oxidative stress (Zhang et al. 2013; Ciftci et al. 2015). This result was obtained from human lung cancer cell line A549. Although the evidence is sparse and not straightforward, the rich sources of food and supplements make it a good candidate for research and drug development.

2.8 Resveratrol

In 1940, Takaoka isolated Res (3,5,4′-trihydroxystilbene) from the roots of white hellebore (Veratrum grandiflorum O. Loes) (Takaoka 1940). Later, Nonomura et al. separated Res from the roots of Polygonum cupsidatum (Fig. 18.2g), a Chinese and Japanese medicinal plant in 1963 (Nonomura et al. 1963). As a polyphenol antioxidant, Res is thought to possess therapeutic potential for the treatment of AD (Tredici et al. 1999; Ranney and Petro 2009). Res (10–100 μM, Fig. 18.2h) performs its influence on AD pathological markers through different mechanisms, including reducing oxidative stress, promoting clearance of Aβ, and activating the anti-amyloidogenic cleavage of β-amyloid precursor protein (Marambaud et al. 2005; Huang et al. 2011; Richard et al. 2011).

Res was reported to be a natural formaldehyde trap (Tyihák et al. 1998) that decreases the cytotoxicity of formaldehyde dependent on cell line and time (Marcsek et al. 2007). Res plays a role in formaldehyde metabolism and is also an estrogen receptor agonist in MCF-7 cells. He et al. investigated the effects of Res on the viability of N2a cells upon FA exposure since N2a, a mouse neuroblastoma cell line, is commonly used to study neurotoxicity (Lepage et al. 2005). They observed that Res dramatically decreases cell apoptosis rates by countering the formaldehyde-induced cytotoxicity and Tau hyperphosphorylation (He et al. 2016).

Further study demonstrated Res inhibits Tau phosphorylation at Thr181 in a dose-dependent manner through suppression of GSK-3β and calmodulin-dependent protein kinase II (CaMKII) activities (He et al. 2016). These two kinases are frequently implicated in Tau hyperphosphorylation in the AD brain (Wang et al. 2013). Moreover, Res is able to increase the activity of phosphoseryl/phosphothreonyl proteinphosphatase-2A (PP2A) in the presence of formaldehyde. These possible mechanisms underlying the neuroprotective effects of Res on FA-induced impairment give an insight into the AD treatment via prevention of Tau from hyperphosphorylation by inhibition of GSK-3β and CaMKII as well as enhancement of dephosphorylation by the activation of PP2A.

2.9 Tetrahydroxystilbene Glucoside

2,3,5,4’-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is the major active component of Chinese herb, Polygonum multiflorum, having tuberous root. Its effects have been tested in multiple dementia or AD-like animal models. The treatment of different chemicals-induced AD models with TSG approach reinforces their learning and memory capacities. In the APPV717I transgenic mice, quantification of amyloid plaques, Aβ content, and Presenilin-1 expression were all reduced following TSG administration (Zhang et al. 2006a, b). TSG could also alleviate learning and memory deficits in Aβ40-induced (Chu et al. 2006), aluminum-induced (Luo et al. 2009), and sodium azide-induced (Zhang 2010) AD-like models. These studies suggest that TSG may function on multiple targets implicated in the complicated pathogenesis of AD. Enhancing cholinergic function, inhibiting Aβ cascade, and protecting synapses and mitochondria may have synergistic outcomes to prevent the dementia loss and neuronal injury (Zhou et al. 2012; Hou et al. 2011).

2.10 Cornel Iridoid Glycoside

More than ten water-soluble components, purified from the sarcocarp of Cornus officinalis, are classified as cornel iridoid glycoside (CIG). This extract offers a breadth of biological benefits, especially for the central nervous system. In an AD model with injured hippocampus cholinergic neurons, learning and memory ability, as well as neuronal cell loss were recovered after CIG treatment. CIG significantly elevated expressions of nerve growth factor, TrkA, and brain-derived neurotropic factor (BDNF), SYP and GAP-43, which are beneficial to the neuron survival and axon growth (Zhao et al. 2010; Ding et al. 2010). As for human neuroblastoma SK-N-SH cells, in the presence of wortmannin, a phosphatidylinositol-3 kinase (PI3K) inhibitor, and GF-109203X, a protein kinase-C inhibitor, CIG treatment could attenuate Tau hyperphosphorylation, improve cell morphology, and reduce microtubule cytoskeleton damage (Yang et al. 2013).

2.11 Cassia Obtusifolia

The seeds of Cassia obtusifolia (CO) was traditionally applied as a herbal remedy for acute inflammatory diseases. About a decade ago, the ethanolic part of the seeds (COE) has been shown to attenuate memory impairments in mice (Kim et al. 2007). Drever et al. studied the effects of COE with calcium dysregulation and cell death models in mouse primary hippocampal cultures, and showed mechanisms for the therapeutic use of COE in the treatment of neurodegenerative disorders (Drever et al. 2008). Yi et al. found that COE has neuroprotective activities against Aβ-induced brain disorders (Yi et al. 2016). Jung et al. demonstrated that the neuroprotective effects of Cassiae seeds are attributable to its anti-inflammatory actions in ischemic stroke and AD models (Jung et al. 2016). Levels of endogenous formaldehyde are higher in cells during oxidative stress and in the brains of mice with ischemic stroke (Chen et al. 2017a, b) and CO could decrease formaldehyde during oxidative stress and ischemic stroke because of its inhibition of inflammation.

2.12 Cinnamon

Cinnamon is a spice obtained from the inner bark of several tree species from the genus Cinnamomum. In traditional Chinese medicine, cinnamon has been long known for its capacity to treat and prevent a wider range of ailments. It has antioxidant, antibiotic, anti-inflammatory properties, and might be beneficial to heart disease, Alzheimer’s disease, and cancer. Cinnamon could also improve cognitive performance in formaldehyde-treated rats by disrupting Tau hyperphosphorylation, inflammatory cytokines, and nuclear damage. Sayad et al. showed that application of 200 mg/kg methanolic cinnamon extract (CE) can significantly improve the performance of rats in Morris water maze test, decrease the levels of phospho-Tau (Thr231), caspase-8, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), as well as reduce the ratio of apoptotic to intact neurons (Sayad-Fathi et al. 2020).

2.13 Astragalus Polysaccharide

Astragalus polysaccharide (APS) is the most important natural active component of Astragalus membranaceus, which is used as a Qi-tonifying herb in traditional Chinese medicine (Yeung et al. 2011). It possesses multiple pharmacological properties, including the regulation of immune function, antiaging, antioxidation, and antitumor properties. In addition, it has been found that APS can protect human bone marrow mesenchymal stem cells (BMSCs) from cytotoxicity and genotoxicity induced by formaldehyde (She et al. 2021). The cytotoxicity, DNA strand breakage, DPCs, and micronucleus levels were all relieved significantly in cells incubated with formaldehyde and increasing concentrations of APS. The mechanism may be associated with upregulation of XPA, XPC, ERCC1, RPA1, and RPA2 in the nucleotide excision repair (NER) pathway, which promotes DNA damage repair. Mesenchymal stem cells can differentiate to neural precursors and/or mature neurons. It represents a promising tool in regenerative medicine. The protection of APS against formaldehyde-induced DNA damage suggests that APS has the potential to mitigate the toxicity of formaldehyde to the brain.

2.14 Mangiferin

Mangiferin (MGF) functions in neuroprotective effect against formaldehyde-induced cognitive impairment of mice. MGF is able to prevent HT22 cell from damage by repressing the cross-talk between ERS and downstream Tau-associated kinases (CaMKII and GSK-3β). MGF may be considered as a potential drug to target the related kinases in the treatment of AD and diseases caused by formaldehyde exposure (Chen et al. 2023).

3 Candidate Compounds Intervening with Formaldehyde

Antioxidants are molecules that can interact with free radicals to prevent or slow down cellular damage. During normal metabolic processes, the free radicals that cause oxidative stress can be neutralized by the body’s endogenous antioxidant system thus achieving homeostasis and balance. In the above section, it is mentioned that formaldehyde itself is a quite reactive chemical and can cause oxidative damage to cells or tissues. Therefore, the application of antioxidants may have the potential to reduce the toxicity of formaldehyde.

3.1 N-Acetyl Cysteine

N-acetyl cysteine (NAC, Fig. 18.3a) is one common antioxidant. It is a precursor of glutathione, an endogenous chemical with thiol group and antioxidant activity. It can also be used as medication for acetaminophen overdose, mucolytic therapy, psychiatry, and other diseases. In animal experiments, formaldehyde was intraperitoneally injected into ICR male mice for 1 week, and the performances of water maze task in both the learning and memory periods were poor. It was indicated formaldehyde accumulation would impair the learning and memory capability. When NAC was supplemented, it significantly improved the performance of formaldehyde-treated mice (Feng et al. 2008). In addition, NAC shows beneficial effects on damages in human lung epithelial cells and osteoblastic cells induced by formaldehyde (Huang et al. 2005; Wang et al. 2014).

Fig. 18.3

The molecular structures of antioxidant to protect against formaldehyde-induced neuronal damage. (a) N-acetyl cysteine (NAC); (b) Vitamin E; (c) Melatonin; (d–f) Omega-3 polyunsaturated fatty acid (ALA, EPA, and DHA). (g, h) EGCG and Thymoquinone

3.2 Vitamin E

Vitamin E (VE, Fig. 18.3b) is a renowned antioxidant that functions as a peroxyl radical scavenger. It is a family of compounds that includes both tocopherols and tocotrienols. They are fat insoluble and readily incorporated into cell membranes to protect them from oxidative damage. According to a study, VE treatment improved the performance of formaldehyde-treated mice in the water maze task (Zhao et al. 2008), which suggested that the antioxidant agency can restore the disruption of formaldehyde-induced learning and memory ability.

3.3 Melatonin

Melatonin (Fig. 18.3c) is a hormone secreted by the pineal gland in the brain. It maintains the circadian rhythm of the body and regulates the release of female reproductive hormones. However, it is also found in bacteria, plants, and unicellular organisms that do not have the pineal gland. Ample studies have demonstrated that melatonin functions as an antioxidant (Reiter et al. 2005). Prefrontal cortex, like hippocampus, fulfills a fundamental role in short-term and working memory (Preston and Eichenbaum 2013). Melatonin is protective against formaldehyde-induced neurotoxicity in prefrontal cortex (Zararsiz et al. 2007). In the meantime, the activities of SOD and GSH-Px increased and MDA levels decreased after melatonin treatment. Moreover, melatonin also prevents the rat testes from formaldehyde-induced oxidative damage and apoptosis (Ozen et al. 2008). In the experiments simulating occupational formaldehyde exposure, Mei et al. observed a decrease of melatonin in the mouse brain with cognitive impairment. Their work suggests that the addition of melatonin may be beneficial for individuals who are normally exposed to formaldehyde in the workplace (Mei et al. 2016).

3.4 Selenium

Selenium is an essential trace element and a constituent of several selenoproteins and enzymes, such as GSH-Px, thioredoxin reductase, and other peroxidases, which are responsible for the antioxidant activity of selenium. Shi et al. found that selenium pretreatment attenuated formaldehyde-induced DPCs’ production in A549 cell line and counteracted the formaldehyde-induced oxidative stress (Shi et al. 2014). In fact, the selenium content in our bodies is quite low and becomes toxic if taken in excess. For this reason, the selenium supplementation requires serious consideration.

3.5 Omega-3 Fatty Acids

Omega-3 fatty acids are polyunsaturated fatty acids and include α-linolenic acid (ALA, Fig. 18.3d), found in plant foods, and eicosapentaenoic acid (EPA, Fig. 18.3e) and docosahexaenoic acid (DHA, Fig. 18.3f) found in fish. Omega-3 is beneficial in treating heart diseases, rheumatoid arthritis, asthma, and Crohn’s disease (Defilippis et al. 2010; Gil et al. 2012). A human study showed that taking omega-3 supplements enhances the antioxidant defense system in patients with type 2 diabetes and probably prevents diabetes complications and related disease progress (Hajianfar et al. 2013). It is comforting that after 10% formaldehyde intraperitoneal injection for 14 days, the activities of catalase (CAT) and SOD of cerebellum decreased while the administration of omega-3 fatty acids alleviated the excessive free radicals (Zararsiz et al. 2011). Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid with diverse health benefits, including boosting learning and memory. Formaldehyde has a significant effect on learning and memory. A slight protective effect of DHA against formaldehyde-induced learning and memory impairment has been identified in Drosophila melanogaster when formaldehyde was ingested (Hua et al. 2021). As mammals are incapable of synthesizing omega-3 fatty acids, omega-3 from food is of great value to our body. It can be used as a source of potential food supplements to prevent the adverse effects of exposure to formaldehyde.

3.6 Epigallocatechin-3-Gallate

Epigallocatechin-3-gallate (EGCG, Fig. 18.3g) is a phenolic antioxidant identified in a number of plants such as green and black tea. It inhibits cellular oxidation and prevents free radical damage to cells. EGCG has also been shown to demonstrate physiological protective functions particularly in the nervous system, in epidemiological and animal studies. Formaldehyde-induced neurotoxicity and cognitive impairment in mice were attenuated after administration of EGCG as a protective agent (Huang et al. 2018). In addition, EGCG can activate Nrf2 signaling pathway and reverse the oxidative damage caused by formaldehyde.

3.7 Thymoquinone

Thymoquinone (Fig. 18.3h) is a phytochemical compound found in the plant Nigella sativa. Thymoquinone has been characterized as having hepatoprotective, anti-inflammatory, antioxidant, anticytotoxic and anticancer activities. It was reported that Thymoquinone could also restore neurotoxic damage induced by agroformaldehyde in the hippocampal region of rats (Saygin et al. 2018).

3.8 Matricaria chamomilla Extracts

Matricaria chamomilla (MC) is a cultivated plant that grows in certain regions of Iran. According to studies, extracts of MC have antibacterial, antioxidant, anti-inflammatory, and anticancer properties. Studies by Sayyar et al. have shown that ethanolic extract of MC can improve formaldehyde-induced memory impairment in rats by reducing cell death and MDA radical activity in the hippocampal region and increasing total antioxidant capacity (Sayyar et al. 2018).

3.9 Astaxanthin

As described by Queen et al. (2024), they have observed the effect of astaxanthin in relation to facilitating neuroprotection, improving cognitive function, and slowing neurodegeneration within given contexts. PEGylated-liposomal astaxanthin can scavenge endogenous formaldehyde and ameliorate Aβ neurotoxicity in the brain of mice (Gu et al. 2024).

4 Hydrogen Sulfide

Accumulating evidence shows that hydrogen sulfide (H₂S) can be produced enzymatically in all mammalian species including human (Li et al. 2011). It may function as a third gaseous signaling molecule participating in a wide range of physiological processes (Modis et al. 2013). Abnormally increased or decreased endogenous H₂S production is associated with various diseases involving the cardiovascular, endocrine, gastrointestinal, and nervous systems (Wallace and Wang 2015). Endogenous formaldehyde accumulation in brain will result in memory-deteriorating diseases such as age-related dementia. It has been demonstrated that endogenous FA inhibits the expression of cystathionine beta-synthase (CBS), the predominant H₂S-generating enzyme, and decreases the production of endogenous H₂S rat in hippocampus (Tang et al. 2013a, b). Excess of nitric oxide inhibits the CBS activity in the central nervous system. However, specific inhibitor of nitric oxide synthase significantly attenuates FA-induced decreases in endogenous H₂S generation, neurotoxicity, and intracellular reactive oxygen species (ROS) accumulation in PC12 cells (Tang et al. 2013a, b) indicating that controls of endogenous H₂S may be a suitable novel therapeutic management for FA-induced neurotoxicity.

Hydrogen sulfide also has cytoprotective effects on neurons and cardiac muscle against oxidative stress and ischemia-reperfusion injury, respectively (Kimura et al. 2012). Tang et al. first reported that H₂S shields PC12 cells from formaldehyde-induced cytotoxicity and apoptosis, an effect related to attenuation of ROS accumulation, preserving mitochondrial function and pro-apoptotic genes expression (Tang et al. 2012). Endoplasmic reticulum (ER) stress is correlated to formaldehyde-induced neurotoxicity. To study the underlying mechanism of hydrogen sulfide protection, ER stress and SIRT-1 expression were assessed (Li et al. 2014). The result showed that protective capability of H₂S is due to overcoming ER stress via upregulation of SIRT-1. BDNF signaling has been extensively studied for its neuroprotective properties. Jiang et al. confirmed that BDNF–TrkB pathway is also involved in the neuroprotection of H₂S against FA-induced cytotoxicity (Jiang et al. 2015). In addition, it has been showed that H₂S can significantly reverse the learning and memory defect of rats in the Morris water maze test, the mechanism of which involve the reduction of hippocampal oxidative damage and apoptosis as well as upregulation of hippocampal BDNF (Li et al. 2020a, b). Both in vitro and in vivo assays showed that BDNF play crucial roles in the H₂S protection.

Additional mechanisms have been documented concerning the efficacy of hydrogen sulfide on FA-induced neurotoxicity. Leptin signaling has antiaging function and H₂S was confirmed to downregulate the expressions of P16INK4a and P21CIP1 via reversing FA-downregulated leptin signaling in HT-22 cells (Zhu et al. 2019). Moreover, aldehyde-dehydrogenase-2 (ALDH2) plays a major role in detoxification of reactive aldehyde in multiple organs and cell types. The study of Chen et al. showed that H₂S could antagonize FA-induced neurotoxicity by downregulating of ALDH2 in PC12 (Chen et al. 2017a, b). That is, the H₂S generation can protect the formaldehyde-induced neurotoxicity by several signaling pathways (Fig. 18.4).

Fig. 18.4

The mechanisms of the action of H₂S on the formaldehyde-induced neurotoxicity

Recently, drug research and development based on H₂S has attracted much attention as it can exert crucial effects on a wide range of cellular signaling processes. Some are currently in clinical trials. But more evidence on animals and human is required before people start using H₂S to treat against formaldehyde-induced CNS disorder.

5 Alcohol Treatments

Formaldehyde, rather than methanol and formic acid, could induce microtubule dissociation and Tau protein hyperphosphorylation, while methanol and formic acid cannot produce such effects. It is indicated that formaldehyde-induced neurodegeneration is in close relationship with contribution to the progression of Alzheimer’s disease. Nonetheless, in two back-to-back papers in 2014, Yang et al. found that chronic methanol exposure in rats and rhesus monkeys induced AD-like symptoms through behavioral experiments and immunohistochemical analysis (Yang et al. 2014a, b). Therefore, formaldehyde may be involved in methanol-induced memory loss.

It is known that methanol acute poisoning can be treated with ethanol. In our body, methanol can be converted into formaldehyde by alcohol dehydrogenase. Application of ethanol reduces the action of alcohol dehydrogenase on methanol by competitive inhibition, so methanol is excreted by the kidneys rather than being transformed into toxic metabolite. Here we suggest that alcohol treatment may be a feasible method to alleviate the memory loss caused by methanol and its metabolite formaldehyde.

6 Water Intake or Tea Drink

Chronic dehydration is a common symptom in patients with dementia. This may result in a feeling of declined thirst and memory loss. Besides, dehydration can trigger formaldehyde accumulation and hyperosmotic stress, both of which will lead to cognitive impairment. In mice, the frequency and quantity of drinking decreased with aging. When mice were water fast but fed with food for 72 h, the brain formaldehyde level increased (Li et al. 2012). The accumulation of endogenous formaldehyde is related with aging and some memory deteriorating disease. It is reasonable that drinking decreases the concentration of endogenous formaldehyde and is beneficial to the excretion of formaldehyde and formate. Regular water or tea intake relieves chronic dehydration and decreases formaldehyde level, which may protect the brain and prevent other diseases. It is recommended to intake water or tea (~200 mL/each time, ~1500 mL daily) during any periods in 1 day including time after getting up, morning, afternoon, and before sleep.

7 Renal Dialysis

According to physical property, formaldehyde is a small gaseous molecule and can permeate and diffuse easily. The formaldehyde level in the blood increased with aging-related dementia. Blood dialysis is a possible way to decrease the concentration of formaldehyde. But there is one concern that the setup of dialysis is usually disinfected with formalin, and the residual formaldehyde may have the opposite action (Klein 1986). More evidences and practices are required to assess the effectiveness and safety of renal dialysis on the formaldehyde removal.

8 Others

Several compounds contained in food or some clinical drugs have also been explored to counteract the formaldehyde-induced memory loss and oxidative damage. We will briefly introduce them to spark discussion. Triphlorethol-A (Fig. 18.5a), an open-chain trimer of phloroglucinol, is a phlorotannin component isolated from Ecklonia cava. It was reported to exert a cytoprotective effect against oxidative stress induced by ultraviolet，γ-ray radiation, and H₂O₂ (Tierney et al. 2010). Zhang et al. have found that it can prevent lung fibroblast cells from formaldehyde-induced cell damage and apoptosis via mitochondria-mediated pathway (Zhang et al. 2010). Moreover, it also protects cells from formaldehyde-induced DNA damage through the PI3K/Akt pathway (Zhang et al. 2011).

Fig. 18.5

The potential chemicals to antagonize the adverse effects caused by formaldehyde exposure. (a) Triphlorethol-A; (b) Caffeic acid phenethyl ester; (c) Theophylline; (d) Metformin; (e) Phenelzine

Caffeic acid phenethyl ester (CAPE, Fig. 18.5b) is a natural phenolic chemical compound of propolis extract. It has antimicrobial, antioxidant, anti-inflammatory, and cytotoxic properties (Murtaza et al. 2014). Formaldehyde-induced neurotoxicity could be blocked by CAPE (Ozdem Turkoglu et al. 2007). Theophylline (Fig. 18.5c) is a phytonutrient found in large quantities in green and black tea. It is widely used in treatment for respiratory diseases. In Morris water maze test, it was demonstrated to attenuate memory loss induced by formaldehyde in mice and increase the activities of SOD in brain (Hao et al. 2008).

Metformin (Fig. 18.5d) is the most commonly used medication for the treatment of type 2 diabetes. It also has potential benefit in cancer prevention and treatment. Mai et al. found that metformin could attenuate formaldehyde-induced bovine serum albumin cross-linking as well as DNA damage in HepG2 cells. It showed that metformin can repair protein and DNA damage induced by formaldehyde at least partly through a direct reaction process (Mai et al. 2020). Another clinical drug for antidepressant, phenelzine (Fig. 18.5e), was reported to protect rat primary cortical neurons and astrocytes from formaldehyde-induced toxicity (Song et al. 2010). It is a monoamine oxidase inhibitor and semicarbazide-sensitive amine oxidase converts methylamine to formaldehyde. The protective effect of phenelzine is thought to be owing, at least in part, to its ability to sequester reactive formaldehyde.

Moreover, peptide and protein drugs show new possibilities to counteract the formaldehyde-induced neuronal toxicity. HSP70 is a member of conserved ubiquitously expressed heat shock protein family that can operate to protect cells from oxidative stress. When it was overexpressed in human bronchial epithelium cells, the harm of formaldehyde exposure was reduced and the DPC content decreased (Duan 2011). It was suggested that targeting HSP70 may be a potential method to handle formaldehyde exposure injury. Carnosine is a dipeptide molecule, made up of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues. It has been established that carnosine can scavenge ROS formed from peroxidation of cell membrane fatty acids under oxidative stress. When treated with formaldehyde, the betatrophin and total antioxidant status levels decreased in kidney, liver, and plasma in rats, while carnosine supplementation reversed oxidative damage caused by formaldehyde (Akkoc et al. 2020), which suggested that carnosine treatment may be useful for protecting persons exposed to formaldehyde.

Lumbrokinase (Earthworm Proteases)

Lumbrokinase (LK) is able to not only enhance blood circulation, but also improve the brain microcirculation. It is beneficial to the elimination of formaldehyde (formic acid) and regulation of the related metabolism. Lumbrokinase (Longshutai) may be worth recommending for improvement of brain microcirculation and intervention of age-related cognitive impairment resulting from aldehyde dysmetabolism (Wang et al. 2019). Furthermore, one patient (74-year-old male) with Parkinson’s disease took one oral capsule of 250 mg LK (30–60 min after dinner, daily) for 6 weeks. His muscle stiffness like Parkinson’s disease symptom was significantly alleviated. Of course, determining the effect of LK (Longshutai) on Parkinson’s disease needs further large-scale clinical trials.

Head Massage Daily

The skin on the top of the human head is approximately 2 mm thick, and the brain’s lymphatic system is distributed within the sagittal sinus, dura mater, and arachnoid. Cerebrospinal fluid enters the lymphatic system and merges with the blood circulation. Head massage, by stimulating the skull or key acupoints, can promote blood flow in the brain. We propose that brain massage not only enhances cerebral blood circulation but also facilitates lymphatic flow, aiding the clearance of brain metabolites such as formaldehyde, formic acid, Aβ, and pTau. Therefore, we recommend daily self-massage for the elderly, including those in the preclinical and mild cognitive impairment (MCI) stages, to support cerebral lymphatic and blood circulation and help prevent age-related cognitive decline (Da Mesquita et al. 2018). Evidence suggests that improving cerebral lymphatic and blood flow can alleviate symptoms of Alzheimer’s disease (AD) (Xie et al. 2024; Ren and Ye 2024).

9 Conclusion

Increasing numbers of individuals are afflicted with age-related cognitive impairment, including Alzheimer’s disease. There are currently no viable treatments for this condition. Formaldehyde is acknowledged to be one of the key risk factors involved in the senile dementia disease. In this chapter, we discuss several interventions, including Chinese medicine, antioxidant chemicals, dietary modifications, and physical therapy, and present additional details. The mechanisms of traditional medicine were compared with modern drugs (Fig. 18.6). The TCM has the characteristic of multiple targets and functions while the modern drug with antioxidant activity can protect the cells from formaldehyde-induced cell death and genotoxicity. In the last section, some chemicals from food or clinical drugs were discussed but they only represent the potential candidate and more investigations are needed.

Fig. 18.6

The mechanisms of actions of Chinese medicine and modern drugs

In recent years, in formaldehyde-treated cells and animals such as rodents and monkeys in which it occurs, protein aberrant modification and aggregation in brain as well as cognitive impairment were employed as common and useful models in drug studies. For example, the extract of Cinnamomum zeylanicum bark was used to improve formaldehyde-induced neurotoxicity through reduction of phospho-Tau (Thr231), inflammation, and apoptosis (Sayad-Fathi et al. 2020). It is known that curcumin is able to modulate the phosphorylation of Tau protein, showing the neuroprotective potency. Dubey et al. combined curcumin with artemisinin (Cur-Art) to restore the impaired nuclear transport in formaldehyde-stressed cells, suggesting Cur-Art’s therapeutic potential against phosphorylated Tau in Alzheimer’s disease (Dubey et al. 2023). Silibinin was also revealed to ameliorate formaldehyde-induced cognitive impairment by suppressing oxidative stress in animal experiments (Wei et al. 2022). As could be expected, more drugs and agents will be investigated and released to decrease or inhibit formaldehyde-induced cytotoxicity and cognitive impairment in the future.

Herein, we proposed one comprehensive program to prevent and treat age-related dementia: from altering diet behavior to the chemical intervention and from Western medical diagnostics to Chinese medicine prescriptions to other style collaborations (Fig. 18.7). All these treatments can be employed to prevent or resist the formaldehyde-induced brain damage or disease. This systemic action and intervention will hopefully benefit the aged people by delaying the onset of dementia and slowing its development process.

Fig. 18.7

The intervention approach to formaldehyde-induced brain damage or disease

Acknowledgments

All grants supporting this project are listed in the Preface of this book.

Competing Financial Interests

The authors declare no competing financial interests.

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Index

A

Aberrant modification55

Aβ40284, 452, 480

Aβ42332

Aβ aggregation333–335

Aβ deposition404, 409, 417, 420, 424

Aβ fibrillogenesis405, 418

Aβ oligomerization405, 418

Aβ plaque181

AβPPLon/Swemice418

Abnormal lysosomes216

Abundant natural sources3

Acceptable daily intake (ADI)433, 449

Acceptor36, 40

Accumulation269, 270, 275, 277, 279–281

Acetaldehyde270, 419

Acetylacetone436, 437, 439, 444–447, 454

Acetylacetone solution449

Acetylcholine (ACh)180, 313

Acetylcholinesterase (AChE)75

A characteristic pungent3

Acori tatarinowii rhizoma475

Acridine orange (AO)206

Acrolein457

Actin200–202, 206, 208, 218

Activated phenotype333, 334

Active demethylation96

Activity-based fluorescence probe NP-FA332

Acute circulatory disturbance353

Acute dehydration422

Acute myocardial infarction (AMI)43

Adhesives6, 7, 9

AD-like pathologies75

Administration243, 244, 256, 274, 275

AD patients75–77

AD progression75

Adrenaline42

Adrenoceptors81

Adrenocorticosteroid306

Adsorption voltammetry435, 449

Adult hippocampal neurogenesis (AHN)99, 104–105

Advanced glycation end-products (AGEs)103, 270, 375, 421

Advanced glycation end-products (RAGE)335

Aerospace syndrome247

Age-1387, 388

Age-matched controls242, 243, 256

Age-related cognitive impairments171, 175–180

Age-related spatial memory deficits82

Aggregation80, 197–219, 270–272, 277, 279, 283–286, 332, 334, 336, 337

Aging75, 76, 82, 119–122, 124–126, 130, 131, 152, 237, 403, 411, 417, 418, 449

Aging animals403

Aging process76

Air pollution355

Akkermansia175

AKt478, 490

Alcohol35, 51, 419, 441, 488

Alcohol dehydrogenase 1 (ADH1)32–35

Alcohol dehydrogenase 3 (ADH3)33, 49–52, 126, 145, 313, 412, 418, 422

Alcohol dehydrogenase 5 (ADH5)140–142, 246

Alcohol dehydrogenases (ADH)387, 388, 412, 488

Aldehyde dehydrogenase (ALDH)419

Aldehyde dehydrogenase 2 (ALDH2)33, 49–51, 53, 372, 375

Aldehyde groups38

Aldehydes126, 129, 270, 283

Aldh2−/− mice419

Aldosterone (ALD)126

Alismatis rhizoma475

AlkB33, 34, 48

AlkB homolog 5 (ALKBH5)97

Alois Alzheimer269

α-amino acids43

α-/ε-amino groups198, 212, 213

α1-antichymotrypsin (ACT)337

α-ketoglutarate97–99

α-linolenic acid (ALA)483, 484

α2-macroglobulin (α2-M)337

Alpha-N-methylation76

Alpha-synuclein81

Aluminum-formaldehyde (ALFA)75

Alzheimer’s disease (AD)35, 42–45, 47, 48, 50, 52, 54, 57, 58, 74, 122, 123, 125, 126, 144, 169, 171–177, 179–181, 183–186, 197, 203, 205, 207, 209, 210, 216, 217, 232, 234, 237, 239–245, 248, 249, 252–256, 269–272, 275–280, 283–286, 329–339, 351, 352, 360, 369–371, 375, 404, 406, 407, 409, 410, 412, 416–421, 423, 424, 451–453, 472–475, 478–482, 488, 491, 492

Amine oxidases98

4-amino hydrazine-5-mercapto-1,2,4-triazole (AHMT)437

Ammonia (NH₃)42, 48, 351, 355

Ampicillin436, 452, 453

Amyloid123, 130

Amyloid beta (Aβ)269–286, 375, 472

Amyloid beta₁₋₄₀54, 283

Amyloid deposition175

Amyloid fibrils200, 212

Amyloid precursor protein (APP)100, 101, 125

Amyotrophic lateral sclerosis (ALS)300, 310, 311

Anaphylaxis299

An energy source in some yeast15

Anesthesia270

Angiotensin II (ANG II)126

Angiotensin-converting enzyme (ACE)355

Angiotensin II type 1 receptor (AT1R)355

8-anilino-1-naphthalenesulfonic acid (ANS)209

Animal behavior73

Animal models270, 284, 403, 411–424

Annexin V and propidium iodide staining213

Anorexia121

Antagonists76

Anthropogenic sources3, 5–6

Antibiotics214, 333, 481

Anti-inflammatory183, 186, 478, 481, 485, 490

Antioxidative186

Antiseptics6

Anxiety123, 129, 299–301, 304–308, 310, 313–316

Anxiety- and depression-like behaviors181

Anxiety-like mood129

AP-1479

A375P cells140, 142, 390

Apium graveolens476

APOE4269–286

Apolipoprotein E269, 284

Apoptosis123, 138, 140, 141, 145–150, 152, 153, 305, 309, 314, 390, 391, 478, 479, 484, 486, 487, 490, 491

APP/PS1-transgenic mouse75, 76, 81, 244, 256, 370, 375, 411, 417–418, 452

APP transgenic mice417, 452

Appv717I transgenic mice475, 480

Arginines33, 53, 392

Arginine vasopressin (AVP)126, 127

Arousal76, 79

Artificial boards6

Artificial carpets6

Artificial clothing6

Artificial walls6

Ascitic fluid143

Asparagine53

Aspartame35

Assemble200

Association200, 201, 204–206, 210–212, 218

Asthma14–16

Astroglia329, 330, 339

Astronaut247

Atherosclerosis53, 351–357, 359, 360, 369, 372–373

Atomic force microscope (AFM)204, 206, 210–213, 215

Atrophy237, 248

Attention76, 80–83, 234, 250, 251

Autism311

Autophagy150–151, 153

Axon269, 272, 275, 279

5-azacytidine96

B

Bacillus subtilis169, 183

Bacteria433

Balance423

Bamboo shoot438

BDNF–TrkB486

BDNF–TrkB pathway149, 486

Beads-on-string279

Bean curd438

Behaviors299, 300, 303–313

Berberidaceae476

β-amyloid315

β-amyloid deposit75

β-sheet54

β-site APP-cleaving enzyme (BACE1)338

Better OHS system10

Bifidobacteria longum174

Bifidobacterium dentium169, 172, 173

Biochemical compounds37–41

Biogenic amines76

Biological decomposition3

Biological metabolism16

Biological processes270

Biological rhythm300, 303, 304

Biomacromolecules216

Biomarkers38, 47, 57, 125

Blood73, 76, 77, 434, 436, 439, 441, 447, 451–453

Blood–brain barrier (BBB)168, 176, 332, 333, 336–339

Blood coagulation353

Blood infarction352, 353

Blood pressure74

Blood vessels354–359

Body74, 82

Body mass index97

Body weight433, 449

Borax buffer75

Bovine serum albumin (BSA)94, 103, 204, 205, 209, 212, 213

Brain433, 436, 444, 447, 449, 451, 452, 455–457

Brain-derived neurotropic factor (BDNF)480, 486

Brain formaldehyde409–412, 417, 421, 422

Brain injury351

Brain lesion329, 359

Brain muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1)104

Brain stem451

Brain tissue73, 82

Brain tyrosine hydroxylase levels413

Breathing3, 4, 11

Bushen capsule473, 475

BV2 cells390, 392

C

Caenorhabditis elegans387, 390

Caffeic acid phenethyl ester (CAPS)489, 490

Calfthymus DNA202

Calmodulin-dependent protein kinase II (CaMKII)479, 482

Caloric restriction389

CaMKII Ca²⁺/calmodulin-dependent protein kinase II277

Cancer14, 35, 49, 55, 435, 436, 451, 456, 457

Candle smoke434, 449

Carbohydrates371, 457

Carbon dioxide (CO₂)3, 49, 57

Carbon–hydrogen bond41

Carbon monoxide (CO)376

Carbonyl14, 45, 51, 209, 356–357, 376, 457

5-carboxylcytosine (5caC)96

Carcinogen138

Carcinogenesis139, 141, 152

Carcinogenic effects4

Carcinogenic molecule48

Carcinogenic risks138

Cardiovascular diseases38

Ca²⁺ releasing152

Carpet cleaners6

Caspase335, 373

Caspase 3478

Caspase 9478

Catalase485

Catalytic activity387, 388

Catalyzed 5mC demethylation96

Catecholamine metabolism76

Catecholamine neurotransmitters73–83

Catecholamine-negative75

Catecholamine-positive reactions75

Catecholamines73–79, 82, 127

Catechol-O-methyl transferase (COMT)76, 78, 79

Cell apoptosis272

Cell cycle arrest147

Cell death139, 140, 151, 152, 211, 213, 215, 218, 270, 272, 280, 284, 286

Cell microenvironment233

Cell morphology140

Cell proliferation138–153, 390, 392

Cell senescence150–151, 153

Cellular energy metabolism80–81

Cellular formaldehyde233

Cellular model403, 424

Cellular skeleton272

Cell viability197, 213

Centenarian392

Central heating system9

Central nervous system (CNS)93, 100, 147, 168, 175, 416, 472–474, 480, 486, 488

CNS functions168, 311

Cerebrospinal fluid (CSF)39, 57, 58, 119, 139, 314, 316

Cerebrovascular disorders313

Chaperone199–200

Characteristics3, 101, 129, 178, 198, 236, 241, 256, 283, 337, 353, 374, 409, 420, 453, 475

Chemical7, 11, 14, 16

Chemical cross-linker198

Chemical ionization mass spectrometry436, 449

Chemical modification198, 199

Chemical reagent449

Chemical sensor454

Chemical synthesis16

Chemokines329, 333, 334, 339

China Nutrition Association (CNA)130

Chinese medicine clinics (CMCs)11

Chipboard9

Chlamydophila pneumonia174

Choice reaction time423

Choline metabolic pathway82

Chromatin compaction97

Chromatin dynamics97

Chromatin structure96, 101

Chromosome144

Chromosome damage14

Chronic accumulation57

Chronic activation333

Chronic dehydration121–124, 126, 127, 130

Chronic kidney disease (CKD)122

Chronic latent neuroinflammation175

Chronic vascular disorders419

13C/1H NMR spectroscopy449

Circadian locomotor output cycles Kaput (CLOCK)104

Circadian rhythms299–316

Cistanches herba475

C-JNK pathway149

Clay5

Clinical275, 285, 286

Clinical trial453

Clusterin (CLU)337, 338

Codeine O-demethylase405

Cofactor36, 40, 41, 52

Cognition235, 237, 239, 242, 250

Cognitive abilities94, 100, 105, 106, 232–257, 392, 413, 416, 423, 424

Cognitive behavior422

Cognitive changes97

Cognitive damages138

Cognitive dysfunction99, 101, 104

Cognitive impairments31, 38, 40, 42, 45, 49, 50, 57, 73–83, 93, 94, 97, 99, 102–105, 119–131, 147, 150, 168–186, 232–241, 243–250, 254–256, 270, 275, 276, 279, 283, 285, 286, 300, 311, 313, 315, 369–376, 386, 391, 392, 403, 409, 410, 412, 416, 418, 420, 421, 424, 473–476, 482, 484, 485, 488, 490–492

Cognitive training237

Cohort study310

Colon cancers419

Compensatory mechanism81

Complex202, 204–207, 217

Condensation reaction77

Confocal microscopy455

Conformational changes198

Congo red210, 212, 213

Consciousness250–253, 257

Consciousness impairment250–255

Consecutive oxidation96

Construct materials8, 16

Cornel iridoid glycoside (CIG)480

Cortex tissue damage413

Cosmetics6

Cost of reproduction390

Creatine metabolism pathway351

Cross-linking and polymerizes bio-macromolecules353

Cross-linking reagent53

Cross-linking reaction14

Cross-links3, 53–55, 141, 147, 198, 274, 371–374

Cross-sectional survey249

Culture medium386, 390

Cultured cells96

Cultured neurons81

Curcumin477–479, 491

Curcuminoids478–479

Cyclic 3′,5′-guanosine monophosphate (cGMP)388

Cyclin-dependent kinase 5 (CDK5)277, 278

Cynomolgus macaques144, 146

Cysteine38, 46, 53, 55, 393

Cysteine thiazolidination150

Cytochrome P-450 system40–41

Cytokines329, 330, 333–336, 339

Cytoplasm272–274, 276

Cytosines33, 48, 54, 94–96, 100, 102, 103

Cytoskeleton disassembly142

Cytotoxicity35, 82, 138, 139, 141, 147, 148, 151–152, 197–219, 233, 276

Cytotoxic oligomers80

D

Daf-2387, 388

Daf-16387

Daily life7

Data analysis423

Deamination42, 53, 96

Deamination-dependent BER96

Death4

Decision-making73, 79

Decoration materials8, 16

Deep sleep73

Definition250

Degradation31, 32, 37, 38, 44, 56, 57, 204, 207, 215, 216, 275, 276

Dehydration119–131

Deionized water451

Dementia122, 125, 130, 131, 329, 472, 478, 480, 488, 489, 493

Demethylases34, 48, 82

Demethylation31, 41, 48, 56, 73, 78, 79, 82, 238, 385, 393, 394, 452, 457

Demethylation of DNA15

Demographic characteristics236

Demyelination312

Denaturation of proteins31

Denatured DNA202

Deoxynucleosides198

Dephosphorylation199, 205, 208, 271, 280, 286

Deposition316

Depression74, 121, 123, 127, 299, 300, 304–307, 310, 314–316

Depression-like behavior127

Derivatives168, 170

Detoxification169–171

dFOXO387

Diabetes mellitus (DM)49, 369–376, 404

Diabetic complications370, 372, 376, 419

Diabetic nephropathy374

Diabetic neuropathy369

Diabetic retinopathy370, 373–374

3,5-diacetyl-1,4-dihydrolutidine (DDL)434, 449, 454

Diagnosis240, 241, 256

Dietary exposure5, 6, 12–13

Dietary restriction389

Differential optical absorption spectroscopy (DOAS)441, 449

Digestion content433, 452

Dimer334

Dimethylamines31, 37, 38

Dimethylaminoethanol31, 40

Dimethylarginine dimethylaminohydrolase 1149

Dimethylglycine31, 32, 34, 37, 40

Dimethylglycine dehydrogenase32, 34, 40

2,4-dinitrophenylhydrazine (DNPH)38, 434–438, 440–445, 447, 450–453

2-diphenylacetyl-l,3-indandione-l-hydrazone435

Dishwashing liquids6

Disinfectant3

Dissociation201, 203

Disuccinimidyl suberate (DSS)209

DL-3-butylphthalide473, 476

DNA31, 33, 48, 49, 53–57, 93–97, 99–106, 198, 201–207, 209–212, 217, 218, 269, 271, 273, 274, 279, 385, 393, 394, 405, 418, 420

DNA adducts141, 142, 147, 148, 152

DNA damages138, 139, 141–143, 145, 147–148, 391

DNA demethylation144

DNA double strands204

DNA hyperphosphorylation150

DNA methylation418, 420

DNA methyltransferase (DNMT)95, 100, 101, 420

DNA-protein cross-links (DPCs)141, 147, 198, 357, 479, 481, 484, 490

DNA repair99, 141, 142, 146–148, 152, 393

DNA replication95, 141, 147

DNA strand breaks14

DNA synthesis144

Docosahexaenoic acid (DHA)483–485

Domain199, 201, 205, 206

Dopamine (DA)74, 75, 77–79, 82, 180, 181, 184, 305, 306, 309, 313

Dopamine beta-hydroxylase79

Dose-dependent142

Double-blind experiment233, 241

Double-stranded DNA203–205, 210

Double-strands279

DPX55

D-ribose404, 420–421

Drinking pleasure130

Drosophila245–246, 403, 415, 416, 418

Drosophila melanogaster386, 415

Drosophila mice82

Drug usage270

Duodenum175–177

Dysfunction197, 198, 214, 216, 218

Dysmetabolism5, 175, 177, 179, 182, 185, 186, 232, 234, 238–240, 242–245, 250–252, 254, 270, 286, 304

E

Earthworm fibrinolytic enzyme-II (EFE-II)209

EB staining338

Eicosapentaenoic acid (EPA)483, 484

Electric appliances7

Electric shock129

Electron microscopy (EM)201, 204, 212, 215

Electrophilic carbon55

Electrophoretic mobility shift assay (EMSA)206, 210, 212

Electrophysiological experiments414

Elevated plus maze127

Embalming fluid433

Emission rate8, 9

Emotion304–308, 313

Endogenous272, 279, 284, 286

Endogenous formaldehyde31–52, 54–57, 73, 75, 81, 82, 119, 124–126, 129–131, 138, 139, 141, 143–145, 148, 171, 175, 176, 180, 182, 183, 186, 214–217, 233–250, 252–256, 302, 304, 307, 308, 310, 311, 315, 316, 351, 352, 354, 358, 360, 385, 392, 393, 403, 411, 412, 421–424, 445, 456, 473, 481, 486, 488

Endogenous formaldehyde metabolism94, 106

Endoplasmic reticulum (ER)233

Endothelial cells333, 337, 338, 354–358, 360

Endothelial dysfunction369, 372

Enteric nervous system (ENS)168

Enterica serovar Typhimurium171, 172, 174

Entorhinal cortex269, 283, 285

Environmentally friendly materials10

Environmental Protection Agency (EPA)433, 449

Enzyme-linked immunosorbent assay (ELISA)249

Enzymes94, 96–102

Epidermal growth factor receptor142

Epigenetic changes141

Epigenetic event385, 418

Epigenetic inheritance73

Epigenetic modifications93, 94, 100–102

Epigenetics93–96, 98, 99, 101–105, 270

Epilepsy311

Epimedii folium475

Epinephrine74–80, 82

Epithelial cells11

Epoxides312

Equilibrium449

ER stress145, 149, 152, 486

Escherichia coli (E. coli)171, 183

Estrogen receptor479

Ethanol270, 371

Ethanol dehydrogenase (ADH)100

Ethyl 3-oxobutanoate436

Etiology242, 310, 313

Eukaryotes97

Examination241, 256

Excess31, 45, 49, 50, 53–55, 57

Excessive fatigue423

Excitatory neurotransmitter74

Excitotoxicity145, 150, 152

Ex-GF mice181

Exogenous formaldehyde73, 139

Exogenous gaseous formaldehyde413

Explorative activity307

Exposure limit449

Exposure time11, 15

Extracellular-regulated protein kinase (ERK)142, 143, 148, 152

Extracts473, 475, 478, 480, 481, 485–486, 490, 491

Extragalactic5

Extra learning237

F

Fabric softeners6

Factories5, 11, 16

Familial Alzheimer’s disease (FAD)98, 100

FANCD2141, 148

Fanconi anemia pathway141, 148

Fan-shaped body388

Fatigue299, 301, 307, 308

Fat mass and obesity-associated gene (FTO)97

Fear73, 101, 129, 252

Fe²⁺ dependent AlkB family97

Fe²⁺ dependent enzyme97

Fermitin family member 2 (FERMT2)338

Fibrinogen aggregation356

Fixative3

Fixative reagent198

Flavin adenine dinucleotide (FAD)40

Fluid intake119–122, 130

Fluid restriction122

Fluorescence436, 444, 446–449, 452–457

Fluorescent alkynes443

Fluorescent molecular probe433

Fluorescent probes215, 443, 446–449, 454–457

Folate276

Folic acid421, 422

Food ingredient270

Food preservatives433

Food restriction388

Forced-swimming test127

Formaldehyde (FA)93–106, 119–131, 138–153, 198, 199, 203, 205, 209–218, 232–257, 269–286, 369–376, 392, 393, 434–437, 439–446, 448, 472–493

Formaldehyde abatement14

Formaldehyde accumulation75–77, 82, 234, 237, 245

Formaldehyde-administrated animals403

Formaldehyde-based resins6

Formaldehyde baseline139–145, 152

Formaldehyde capturers140, 152

Formaldehyde coming31

Formaldehyde cross-linked with the lysine²⁸182, 418

Formaldehyde cycle73, 76, 78–80, 82, 94, 95

Formaldehyde dehydrogenase (FDH)33, 41, 46, 49, 51, 52, 100, 241, 245, 246, 387, 424

Formaldehyde dismutase411

Formaldehyde disruptor14, 49, 101, 102, 152, 185, 303, 312, 337–338, 482

Formaldehyde dissimilation/oxidation enzymes170–172

Formaldehyde dysmetabolism168–186

Formaldehyde exposure4–7, 9–11, 14, 15

Formaldehyde fluorescence probe (FAP)406

Formaldehyde gas74

Formaldehyde going31

Formaldehyde-induced 2-aza-Cope454, 455

Formaldehyde induced cytotoxicity479, 486, 492

Formaldehyde-induced fluorescence (FIF)75

Formaldehyde-induced neuronal damage477, 483

Formaldehyde inhalation146, 150, 248

Formaldehyde metabolic enzymes75

Formaldehyde metabolism216, 217, 479

Formaldehyde oxidation/dissimilation170

Formaldehyde probe-1 (FAP-1)454–456

Formaldehyde-protein cross-linkage55

Formaldehyde-related animal models307

Formaldehyde-related cellular models403, 424

Formaldehyde-related molecular models403, 424

Formaldehyde stress240, 278

Formaldehyde vapor74

Formalin-fixed paraffin-embedded (FFPE)198

Formalin solution138

Formate37, 49, 51

Formic acid33, 35, 49, 57, 58, 100, 105, 276, 284, 285, 352, 353, 355, 359, 360, 370, 371, 373, 374

5-formylcytosine (5fC)96

Formyl GSH51

FOXO3478

Free radicals279, 482, 485

Frequency of water-intake120, 125, 126

Frontal cortex synaptosome127

Frontal lobe276, 283

Fruit flies82, 386

F2t-isoprostane353

FTO33, 48

G

Galaxy5

Gamma-aminobutyric acid (GABA)173

Gas chromatography (GC)435, 439, 449, 451

Gaseous molecules15

Gas sensor437, 442, 446, 449, 454

Gene expression93, 94, 97, 98, 100, 101, 103

Gene knockout40

Gene mutation270

General indoor pollutant7

Generation31–48, 53, 55–57

Genetic damage14

Genetic information96

Genetic model386

Geniposide473, 477, 478

Genome-wide association studies (GWAS)334

Genomic instability148, 152

Genotoxic4, 13

Genotoxicity55, 330

Genotoxicity markers15

Germ cell95

Germfree (GF) mice181

Ginsenoside Rg1149

Glass production5

Glial cell hyperactivation75

Glial cells73, 337

Globular-like deposits212, 213, 215

Glomerular basal membrane (GBM)374

Glucocorticoids306

Glucose-regulated protein 78149

Glucosyltransferase96

Glutamate392

Glutamic dehydrogenase (GDH)80, 200

Glutamine53

Glutaraldehyde270

Glutathione (GSH)36, 45–47, 51, 81, 170, 172, 183, 301, 312, 331, 390

Glutathione-dependent formaldehyde-activating enzyme170

Glycan73

Glycated BSA82, 103

Glycation369, 371, 375

Glyceraldehydes33, 39

Glycerol31, 32, 40, 41

Glycine32–34, 37, 39, 40, 43–44

Glycogen synthase kinase (GSK)478, 479

Glycogen synthase kinase 3 beta276–277, 287

Glycolaldehyde439

Glycosylation205, 218

Goldilocks principle392

Golgi apparatus139

G-quadruplex DNAzyme443

Greenhouse gas emissions5

Grooming127

GSH peroxidase (GSHPx)45, 51, 479, 484

GSH reductase (GSHRx)45, 51

GSH S-transferase (GSHST)51

GSH synthesis419

Guanidine-HCl (GdnHCl)199, 200

Gustatory receptor390

Gut bacteria52

Gut barrier dysfunction419

Gut microbiota168–186, 371

Gut microbiota-formaldehyde-brain cassette/axis171

Gut microorganisms186

H

Heat shock388, 389, 394

HeLa cells390

Helicobacter pylori (H. pylori)174

Hematopoiesis14

Hepatocellular carcinoma391

Heterotrophs169

Hexulose-6-phosphate synthase (HPS)169, 171, 172, 186

HIF-1α signaling354

High-confident evidence239

High-frequency electrical stimulation (HFS)414

Highly toxic3

High-performance liquid chromatography (HPLC)/electrochemical procedure11, 38, 54, 215, 240, 249, 250, 274, 386, 404–406, 409–411, 420, 434–437, 439–446, 449–453

Hippocampal AHN99

Hippocampal formaldehyde243, 256

Hippocampal formaldehyde levels410, 414, 415

Hippocampal neural progenitor cells99

Hippocampus269, 274–277, 283, 285, 286, 305, 306, 314, 332, 391, 409–411, 414, 415, 417, 420, 424, 475, 480, 484, 486

Hippocampus-related topographic amnesia103

Histamine312

Histidine37, 53, 55

Histone deacetylase 3 (HDAC3)96

Histone demethylation94

Histones15, 31, 33, 48, 93–95, 97–106, 204, 205, 385, 393, 394, 405, 418, 420

Histopathologic332

Homeostasis31, 57

Homoallylic amine454, 455

Hormesis389

Hospitals238, 252, 300

Host microbiome175

Household products6, 433

HT-29 cells390

Human carcinogen14

Human exposure characterization of chemical substances (HEXPOC)12

HUV-EC-C cells390

Hydrocarbons73

Hydrogen atoms3

Hydrogen peroxide (H₂O₂)35, 38–48, 52, 53, 56, 351

Hydrogen sulfide (H₂S)414, 486–488

6-hydroxydopamine (6-OHDA)76

Hydroxyl radicals35, 46, 47

5-hydroxltryptamine (5-HT)127

5-hydroxymethylcytosine (5hmC)96

Hydroxymethyl55

Hyperglycemia369–371, 373–375

Hyperlipidemia351, 359

Hypermethylated101, 104

Hyperosmotic stress123

Hyperphosphorylation123, 197, 198, 208, 209, 216, 218, 238, 240, 243–245, 269–277, 279–281, 283, 285, 286, 316, 332, 336

Hypertension351, 352, 355–356, 359

Hypocretin-induced arousal80

Hypodiploid DNA145

Hypohalous acids43

Hypoxia-ischemia270

I

Icariin473, 476–478

Imbalance270, 283

Imines53

Immune cells332, 333, 339

Immunocytofluoresence273

Immunofluorescence assay206

Immunohistochemical staining203

Immunological system329

Inactive 3-O-methyl-metabolites78

Incineration3

Indoor exposure7

Indoor pollutants6

Industry433

Inflammation270, 284, 329–331, 333, 334, 336–339, 369

Inflammatory138, 148, 329–339

Inflammatory pain147

Information transmission73

Inhalational3

Inhalation formaldehyde6, 7, 11

Insulation insecticide433

Insulin387, 390

Insulin/IGF-1 pathway387

Interdigitated microelectrode array437, 449

International Agency for Research on Cancer (IARC)449

Intervention179, 180, 218, 244, 301, 316, 424, 469–493

Intestinal flora31, 56

Intestinal microbe flora270

Intestinal microbiota168, 173, 175, 177–179, 184, 186

Intracerebroventricular injection146, 151, 414

Intraperitoneal administration244

Intraperitoneal injection125, 144, 146

Intraperitoneal injection of D-ribose404, 420–421

In vitro93, 103, 105

In vivo270, 274, 277, 283, 433, 450, 452, 456

Ion chromatography434, 449, 450

Ion flow tube mass spectrometry435

Ionized calcium-binding adapter molecule 1 (Iba1)330, 338

Irritability423

Irritating odor3

Irritation301

J

JmjC domain99

JmjC domain containing proteins33, 34, 82

JmjC family proteins98

JTT matrix-based model171

K

K48 polyubiquitination150

KDM182

Keratinocytes312

Kinase276–278

L

Laboratories7, 16

Lachnospiraceae172, 174, 175

Lactate dehydrogenase (LDH)80, 81, 200

Lactobacillus brevis169, 171–173

Lactobacillus fermentum NS9169, 172

Lactobacillus helveticus (L. helveticus)174

Laser printers7

Late-onset AD (LOAD)334

LDH leakage151

L-DOPA the precursor of dopamine181

Learning73, 76, 81, 233, 235, 237, 238, 244–248, 250, 251, 253

Learning and memory474, 475, 478, 480, 482, 484, 485, 487

Left internal mammary artery (LIMA)357

Lesions308

Leukemia14, 15, 140–142, 182, 299, 436, 451

Leukocytes355

LeuLeuOMe215

L. helveticus NS8181, 182

Life cycle386

Lifespan82, 385, 412, 415, 416

Ligusticum chuanxiong hort475

Lime315

Lipid oxidation38

Lipid peroxidation146

Liquid chromatography and electrospray ionization mass spectrometry (LC/MS)53

Living habits9

Loci coerulei (LC)76

Locomotor307

Longevity386, 388, 390, 392, 393

Long noncoding RNAs (lncRNAs)97

Longitudinal studies237

Long-term depression (LTD)277

Long-term drought129

Long-term potentiation (LTP)75, 76, 180, 240, 414, 415, 417

Low temperature409

Lymphocyte202

Lymphopenia391

Lysine33, 39, 48, 55

Lysine demethylases (KDMs)33, 48

Lysine-specific demethylase 1 (LSD-1)33, 34, 98, 99, 143

Lysine-specific demethylase 1A98

Lysine-specific demethylase 5A104

Lysosomes45–47, 56, 57, 139, 149, 270, 314, 406, 443, 455, 456

M

Macaca mulatta275, 416

Magnetic resonance imaging (MRI)249

Major groove204

Malaise301

Malondialdehyde (MDA)38, 39, 146, 331, 376, 404–405, 449, 476, 479, 484, 486

Malondialdehyde-deoxyguanosine (M1dG)353

Mangiferin (MGF)75

Medicines6

Medium-chain dehydrogenase/reductase (MDR)387

Melamine resin6

Melatonin (MT)74, 248, 300–304, 483, 484

Melting temperature202, 279

Memory decline303, 352, 358

Memory deficit331

Memory impairment359, 392

Memory loss127, 130, 332, 338

Metabolic balance120

Metabolic memory99

Metabolic products130, 131

Metabolism31–58, 330, 331, 387, 388, 391, 393

Metabolite270, 272, 276

Metaformaldehyde (MFA)168

Metal ions270

Methane73

Methanol31–37, 40, 49, 56–58, 79, 169, 171, 175, 179, 233, 238, 243, 244, 253, 256, 270, 274–276, 283, 286, 351, 353, 370–373, 376, 386, 434

Methanol-administrated animals403

Methanol exposure488

Methanol metabolism100

Methanotrophic bacteria169, 170

Methionine95

3-methoxy-4-hydroxyphenylglycol (MHPG)81

Methyl acetoacetate440, 445

3-methyl-2-benzothiazolone hydrazone449

5-methylcytosine (5mC)94–96

Methyl donor35, 94, 95, 100

Methyl group donor78, 79

Methyl groups33, 37, 48, 144

Methylamines31, 33, 41–43, 53, 98, 370, 372, 373, 419

Methylases98

Methylated amine98

Methylations35, 48, 78–80, 82, 93–106, 237, 238, 385, 392–394, 452

Methylene37, 53, 54, 77

Methylglyoxal (MGO)376

Methylobacterium extorquens AM1170

Methylol adducts53, 55

Methylotrophic organisms169

Methylotrophs169, 170

Mice386–388, 391–393

Microbe models memory410

Microbiota-gut-brain axis173, 176, 182, 452

Microcirculation270

Microenvironment143

Microfluidic chip439, 449, 454

Microglia174, 329, 330, 333–339

Microglial surface receptor335

Micronucleus frequency11

MicroRNAs (miRNAs)309

Microsomes40, 41

Microtubule197–202, 204, 206, 208, 210, 269, 271, 272, 274, 279, 280

Microtubule-binding domain (MBD)199, 204

Mild cognitive impairment (MCI)241, 248, 251–253, 256, 410, 475, 476, 491

Mild moderate stage123

Mineral water130

Mini-mental status examination (MMSE)125, 130, 369, 423

Misfolding197, 205, 210, 213

Mitochondria37, 40, 49, 51, 56, 57, 82, 139, 146, 149, 151, 391

Mitochondrial damage374

Mitochondrial dysfunction138, 145, 148, 151, 152

MMSE scores241, 242, 249, 256

MoCA scores237

Modifications197, 199, 203, 205, 213, 216

Molecular models403, 424

Monoamine oxidase (MAO)76, 78

Montreal cognitive assessment (MoCA)125, 235, 423

Mood74

Morphogenesis309

Morphology202, 204, 215, 275, 280

Morris water maze (MWM)392, 409, 415, 419, 421, 422

Mortality123, 391

Motor neuron390

Mouse435, 436, 445, 447, 451, 452, 457

Mouse model48, 99, 104, 124, 127, 175, 184, 186, 247, 334, 336, 418, 419

Mouse primary hippocampal cultures480

MPO33, 34, 43–44, 57

MPO-H₂O₂-chloride system43, 44

Multifunctional protein197–219

Multi-target473

Mutants385, 387, 388, 394

N

N2a cells246, 272–274, 277, 278, 280

N-acetyl cysteine (NAC)482, 483

N-acyl-4-sphingosine-1-phosphocholine404

NAD⁺200, 442, 454

NADP oxidoreductase49

Nanogram-scale453

Nanoporous silica aerogel444, 457

Nanoporous silica aerogel sorbent433

Naphthalene-based “Turn-On” fluorescent probe443, 455

Nasal airway141

Nasal mucosa311

Nasal respiratory tissues144

Nasogastric tube administration146

Nasopharyngeal cancer138, 139

Naturally4, 12

Nausea301, 307

Navigation269

NCBI protein171, 172, 186

N-demethylation97

Necrosis138, 151–153

NE deficiency76

Neocortex74

Nerve growth factor480

Neural cell123, 125, 129, 130, 175, 213, 218, 238, 253, 269, 276, 279, 285, 312, 353, 358, 391, 392, 409

Neural differentiation140

Neural maturation140

Neural plasticity94

Neural stem cells (NSCs)104, 140

Neural system390, 392, 394

Neural transmitters180

Neurite274, 276, 280–282

Neuro 2a cell line478

Neuro-2a cells (N2a)405, 408, 421

Neuroblastoma270, 283

Neuroblastoma cells123, 148

Neuroblasts75

Neurodegeneration171, 182–183, 185, 186, 198, 203, 209, 213, 219, 277, 283, 486, 488

Neurodegeneration diseases79, 81, 83, 94, 100, 168, 173, 175, 180–186, 404, 412, 452, 454, 457

Neurodegenerative disorders38, 269, 272, 310, 312

Neurofibrillary tangles (NFTs)206, 216, 269–272, 276, 283, 285, 286, 329, 336

Neurofilament312

Neurogenesis140

Neuroglia314

Neuroinflammation329–339

Neurological disorders16

Neuronal cdc2-like protein kinase (NCLK)200, 209

Neuronal cell death478

Neuronal cells138, 152, 153

Neurons73, 74, 81, 83, 269, 271, 272, 280, 285

Neurophysiology314

Neuroprotective473–476, 478–482, 486, 491

Neuroprotective effects75

Neuropsychological assessment240

Neuropsychological tests423, 452

Neurotoxicity131, 149, 151, 152, 198, 214, 217

Neurotransmitters304, 306, 309, 313, 316, 392, 394

Neurovascular337

Neutrophils43

N6-hydroxymethyladenosine (hm6A)97

Nicotinamide adenine dinucleotide phosphate (NADPH)36, 41

Nitric oxide (NO)391, 418, 476, 486

Nitric oxide synthase (NOS)122

Nitrosylation391, 392

NLRP3334

N6-methyladenosine (m6A)97, 106

N-methyl-D-aspartate (NMDA)332

Nociceptive stimulation147

Non-enzymic process76

Non-human primate276, 285

Noninfectious inflammation331

Noninvasive biomarker241, 249, 256

Non-methylated H3K498

Non-pathological conditions120

Non-regulated sources6, 7

Noradrenaline74

Norepinephrine (NE)74–83, 180–185

Norepinephrinergic neuron loss76

Normal controls (NC)410

Nosebleeds311

Noticeable phenotypes97

NS capsule179, 180

NS lactobacillus179–180

Nuclear fragmentation149

Nuclear magnetic resonance (NMR)54

Nuclear Tau202, 203, 212

Nucleolar organizer region202

Nucleophilic site55

Nucleotide excision repair147

Nucleus273, 276, 277, 279

O

Occupational contact139, 146

Occupational exposure7, 11, 14

Octanol387

Offices exposure9–10

Olfaction308

Olfactory bulb308, 309

Olfactory memory274

Olfactory receptor390

Oligomers54, 198, 203, 214, 334

Omega-3 fatty acids484–485

One carbon circle52

One-carbon compounds169

One-carbon pool94, 98

Open field test127

OR83b390

Oral administration123

Orally50, 254, 351

Outer space5

Oxidation of lipids31, 403, 404, 457

Oxidative96, 97, 104

Oxidative demethylation96–98, 405

Oxidative reaction3

Oxidative resistance388, 389

Oxidative stress31, 38, 41–47, 56, 82, 138, 143, 145–150, 152, 234, 238, 239, 247, 249, 270, 330, 331, 335, 353, 354, 356–360, 369, 371, 373, 389, 404, 405, 407, 410, 414, 419, 455, 478, 479, 481, 482, 484, 486, 489, 490, 492

Oxidoreductases32, 33, 36

2-oxoglutarate (2OG)96

Oxygen99

Oxygen atom3

P

p25278

p35278

Paired helical filaments (PHF)123, 197, 205–207

Panic299

Paraffin-embedded198

Paraformaldehyde (PFA)168

Paraoxonase-1149

Paraquat388

Pared helical filaments (PHFs)271, 272, 280, 287

Parietal lobe276, 283

Parkinson’s disease (PD)74

Partial correlation analysis237

Particle board9, 11

Particles minus 2.5 nanometer (PM2.5)307, 314

Passive demethylation95, 96

Pathogenesis281, 329, 333–335, 338

Pathological272, 274–276, 279–281, 283

Pathological condition82, 331, 352, 370, 404

Pathological dose of formaldehyde407

Pathological features123

Pathology269, 275–277, 283, 285

Pathomechanism232, 242

Patient autopsy256

PC12 cell line486, 487

Pectin34

Performance and cognitive recall423

Perioperation239

Peripheral blood lymphocytes11, 14

Peripheral immune dysfunctions333

Perivascular332, 337

Peroxidase33, 43

Phenelzine489, 490

Phenol–formaldehyde305

Phenol-formaldehyde resin6

Phenotypes333–335

Phentolamine N-methyltransferase (PNMT)76, 79

Phosphate271

Phosphatidylinositol-3 kinase (PI3K)480, 490

6-phospho-3-hexuloisomerase (PHI)169, 171, 172, 186

Phosphorylation142, 147, 149, 199, 203, 205, 209, 214, 218

Photochemical reactions3, 4

Photocopiers7

Physical35, 93, 130, 131, 141, 168, 305, 310, 385, 473, 489, 491

Plants combustion processes3

Plastic laminate plant353

Plywood workers14

Point mutations141

Polarography434, 449

Pollution307, 315, 316

Polyanions198

Polyglutamate198

Polygoni multiflori radix praeparata475

Polymerization273, 285

Polymers273, 274

Polyvinyl alcohol247

Porcine brain451

Poria cum radix pini (PRP)474, 475

Porphyromonas gingivalis vimA410

Positive correlation130

Post hoc Newman–Keuls comparisons235, 236

Post-operation239

Postoperative cognitive dysfunction (POCD)238–240, 256

Postoperative complications239

Post-stroke cognitive impairment (PSCI)352

Post-stroke dementia (PSD)249

Potassium bromate436, 438, 442, 443

Potassium ferricyanide434

Potassium hexacyanoferrate75

Potential risk factor359

Power plants3

Preclinical269, 270, 286

Preconcentration451

Preconcentration-chemical ionization mass spectrometry436, 449

Precursor276

Prefrontal cortex146

Preoptic periventricular nucleus75

Presenilin-1 (PS1)125, 480

Preservative3, 6, 11

Presynaptic release73

Presynaptic vesicles74

Prevalence234

Primary hippocampal neurons140

Primary neurons276

Primary open angle glaucoma (POAG)311

Primitive atmosphere3, 4

Probiotics169–173, 179, 180, 186

Procarcinogens41

Programmed cell death145–152

Proinflammatory factor331

Pro-inflammatory markers331

Promoters94, 100, 101, 103, 104

Promoting transcription93

Prospective cohort studies97

Prostate cancer435, 451

Protection equipment16

Protein aggregations35, 42, 404, 408, 419

Protein crossing linkage42, 53, 283

Protein denaturation31, 37–38

Protein exterior197

Protein glycation369, 373

Protein misfolding80, 197, 213–214, 233

Proteinphosphatase-2A (PP2A)278, 286, 287, 479

Proteins94–98, 100, 101, 106

Protein Tau197–219

Proteotoxicity138, 145, 150, 152

Protocol449

Protofibrils54

Pseudomonas Putida J3411

Pterin cofactors170

Pungent3, 308

Purines39, 54

Q

Quantity of water intake120, 125, 130

Quartz crystal microbalance (QCM)443, 453

R

Radial arm maze127

Radiometric analysis with dimedone 14C449, 451

Rapid fixation353

Rate-limiting enzyme127

Reactive aldehydes313

Reactive oxygen species (ROS)45–47, 143, 148, 202, 203, 331, 333, 334, 370, 373, 388, 407, 486, 490

Receptors73, 76, 79

Recoveries451

Reducing properties14

Reducing sugar decomposition38–39

Reference exposure level (REL)9

Refolding200

Regular water intake131

Relationships168, 175, 183

Relative standard deviations (RSDs)451, 457

Renovated homes248

Reproductive systems4, 15

Residential5, 7–9, 12, 16

Residential renovation8

Resin6, 9, 11, 300, 438, 443

Respiratory299, 300, 312

Respiratory complications239

Respiratory irritation138

Respiratory tract138

Resveratrol130, 140, 179, 388, 473, 477, 479

Retinoic acid391

Rhesus332

Rhesus monkeys283, 284, 286, 403, 416, 417

Rhinitis299, 312

Rhizoma acori tatarinowii (RAT)474, 475

Rhodamine B438

Riboglycated bovine serum albumin94

Ribose82, 103, 369

Ribosomal RNA (rRNA)97, 101

Ribulose monophosphate (RuMP) pathway169, 171

Risk factors202, 215, 217, 237, 239, 248, 253

RNA31, 33, 48, 49, 53–56, 73, 77, 79, 93–97, 99, 100, 102, 105, 106, 201–203, 206–207, 218, 385, 392–394

RNAi388

Rodents276, 279, 389, 391, 392, 403, 411–412, 424

S

S-adenosyl-L-methionine (SAM)35, 78, 79, 94, 95, 98, 104, 105

Salmonella enterica subsp.171, 172, 174

SAMP8 mice42, 46, 51, 52

SAMR1 mice42, 46, 51

Sarcosine (N-methylglycine)31, 40

Sarcosine dehydrogenase33, 34, 40

Sauerbrey equation453

Scaffolding theory237

Schiff bases53, 54, 77

Schiff’s reaction76

Selective norepinephrinergic neurotoxin76

Selenium484

Semicarbazide sensitive amine oxidase (SSAO)31, 33, 41–43, 50, 53, 54, 98, 126, 127, 145, 209, 210, 245, 249, 283, 330, 336, 370, 372, 373, 375, 450

Senescence391, 393, 394

Senescence-accelerated mouse (SAM)412

Senescence-accelerated mouse prone 8 (SAMP8)75, 81, 244, 245

Senescence-accelerated-resistant mice 1 (SAMR1)244, 245

Senescence-prone strain 8 (SAMP8)125

Senescence-prone strains (SAMP)412, 418

Senescence-resistant strain 1 (SAMR1)125

Senescence-resistant strains (SAMR)412

Senile plaques (SPs)123, 174, 175, 206, 243, 244, 269, 281, 283, 315, 416, 417, 419

Senility270

Sensitization307, 308

Ser396272, 273, 275–278

Serine hydroxymethyltransferase (SHMT)32–34, 170–173, 352

Serine8/26 of Aβ405

Serotonin (5-HT)73–75, 180–185, 392

Serotonin reuptake inhibitors (SSRIs)181

Serum osmotic pressure124

Shenwu capsule473, 475

Short-term drought129

Shrank272

SH-SY5Y80

SH-SY5Y cells390, 392

Shuttle box127, 129, 307

Shuttle box assay244

Sick building syndrome (SBS)14

Single-cell methodologies186

Single-strand DNA203

Sir2390

SIRT-1149

Skin contact4

SK-MEL-28 cells390

Smallest aldehyde3

Smallest aldehyde molecule413

Small intestines175–177

Small molecule compound100

Small nuclear RNA (snRNA)97

Smart soup473–475

Smoking14

S-nitrosoglutathione (GSNO)388

S-nitrosoglutathione reductase (GSNOR)388, 391–393, 418

Social relationships390

SOD1390

Sodium concentration124

Spatial learning and memory412, 421

Spatial learning and memory impairments100

Spatial memory301, 315

Spatial memory process414

Spatial recognition274

Spinal cord74

Squamous cell carcinoma141

Stabilization271, 280

Standard curve451

Standard test method450

Starvation270, 388, 389

Starvation resistance388, 389, 392

Steady-state333

Sterile water411

Stimulation278

Strategies130

Stress resistance385–389, 415, 416

Striatum336

Stroke351–360

Substance P (SP)336

Sugar decomposition403, 405

Sugar input388

Sulfated glycosaminoglycans199

Superoxide dismutase (SOD)476, 478, 479, 484, 485, 490

Surface-to-volume ratio454

Sweetener49

Synapses73, 83, 473, 480

Synaptic activities73, 81

Synaptosomal-associated protein 25 (SNAP25)309

Synaptosome306

Syndromes123, 142, 183, 474

Synergistic334

Syntheses276

T

Tail vein injection123, 144

Tau75, 80, 81, 123, 329, 332–334, 336

Tau aggregation197–219

Tau dysfunction80

Tau hyperphosphorylation42, 75, 146, 175, 336, 337, 339, 386

Tauosome202–206, 212

Tau protein375

Tau protein hyperphosphorylation478, 488

Temperature388, 453

Template205, 207

Temporal lobe276, 283

Ten-eleven translocated oncogene (TET)96

TET196

TET296

TET396

Tetrahydro-beta-carbolines75

Tetrahydrobiopterin309

Tetrahydroisoquinolines74

Tetrahydroxystilbene glucoside480

TH-DA-NE cassette181

The emission rate of formaldehyde9

The hydrogenation of CO ice5

The largest chipboard manufacturing12

Thiazolidine-4-carboxylic acid393

Thinking250

Thioflavin S (ThS)270, 273, 287

Thioflavin T (ThT)210, 213

Thiols45, 52, 53

Thirst sensation120, 121, 126

Thr181272, 275–278, 285

Three meals daily129

Tight junctions (TJ)338

Time- and dose-dependent152

Tissue fixation198

Titanium dioxide nanotube array (TiO2-NTA)433, 454

Toxic effects386

Toxicity4, 12–15

Toxicosis13, 213, 238, 419

Toxoplasma gondii (T. gondii)174, 175

Traditional Chinese medicine (TCM)473–482, 491

Transcription93, 94, 96, 98, 100, 101, 103, 104, 202, 206, 207

Transcriptional activation101

Transcription factors385

Transgenic models100

Transient receptor potential ankyrin 1 (TRPA1)336

Transient receptor potential cation channel, subfamily A, member 1 (TRPA1)309

Transient receptor potential vanilloid 1 (TRPV1)336

TREM2335

Trichloroacetic acid453

Trigger38, 45, 54, 123, 150, 153, 175, 183, 207, 239, 277, 286, 335, 354, 407, 443–445, 488

Trimethylamine37, 38

Trimethylamine oxide (TMAO)31–33, 37, 38

Trimethylamine oxide demethylase (TMAO-ase)32–34, 38

Triphlorethol-A489

T7 RNA polymerase207

Tryptophan (Trp)37, 53, 55, 181

Tumor cells144

Tumorigenesis93

Tumor necrosis factor-α (TNF-α)330, 331, 333, 335, 337

Tumors44, 141, 143–145, 152, 185, 270, 299, 310, 406, 457

Type 2 diabetes (T2D)97, 369, 371, 375

Type 3 diabetes (T3D)369

Type 2 diabetes mellitus (T2DM)404

Type A monoamine oxidase (MAO-A)42

Type III alcohol dehydrogenase (ADH III)388

Tyrosine53

Tyrosine hydroxylase (TH)127, 306, 309, 313

U

Ubiquitin272

Ultraviolet detector450

Ultraviolet radiation388

Unpleasant odor14

Urea formaldehyde resin6, 9

Urinary formaldehyde82, 284

Urine75, 279, 285, 286, 302, 307, 308, 316, 410, 420, 423, 434, 437, 444, 451–453, 457

Urine formaldehyde125, 129, 234–242, 249, 250, 256

V

Variable spatial delayed response task (VSDRT)276

Vascular adhesion protein-1 (VAP-1)41, 355–357

Vascular dementia (VaD)125, 232, 237, 240, 244, 245, 249, 256, 283, 351–360, 452, 476

Vascular endothelial cells354

Vascular smooth muscle cells (VSMCs)356, 357

Vascular smooth muscles373

Vasoconstriction74

Vehicle exhaust5

Vehicle’s combustion processes3

Ventilation301, 315

Ventilation facilities16

Vertigo307

Victims13

Visceral pain aversion memory81

Visual fields423

Visual learning388

Visual reproduction423

Vitamin E (VE)482–484

Volatile organic compounds (VOCs)371

W

Wake73, 301

Wakefulness80

Warm boiled water130

Water433, 442–445, 447, 449, 453

Water deprivation124, 126, 128, 129

Water homeostasis119, 122

Water intake488

Water-intake behavior125, 130

Water maze task482, 484

Water maze test244, 246

Winter indoor formaldehyde9

Wood-based furniture6

Wood-based materials6

Working memory484

World Health Organization (WHO)449

“Wormlike” conformation199, 210, 213

X

Xylene300

Y

Y maze127

Y-maze spatial recognition memory test416

Yu fire disturbing474

Z

Zebrafish80

Zeolitic imidazolate framework (ZIF)442

ZO-1338