Formaldehyde, Epigenetics, and Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia. The accumulation of β-amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein are two hallmarks of AD. The β-amyloid and tau proteins have been at the center of AD research and drug development for decades. However, most of the clinical trials targeting β-amyloid have failed. Whereas the safety and efficacy of most tau-targeting drugs have not yet been completely assessed, the first tau aggregation inhibitor, LMTX, failed in a late-stage trial, leading to further recognition of the complexities of AD and reconsideration of the amyloid hypothesis and perhaps the tau hypothesis as well. Multilevel complex interactions between genetic, epigenetic, and environmental factors contribute to the occurrence and progression of AD. Formaldehyde (FA) is a widespread environmental organic pollutant. It is also an endogenous metabolite in the human body. Recent studies suggest that elevation of FA in the body by endogenous and/or exogenous exposure may play important roles in AD development. We have demonstrated that FA reduces lysine acetylation of cytosolic histones, thereby compromising chromatin assembly and resulting in the loss of histone content in chromatin, a conserved feature of aging from yeast to humans. Aging is an important factor for AD progression. Therefore, FA-induced inhibition of chromatin assembly and the loss of histones may contribute to AD initiation and/or development. This review will briefly summarize current knowledge on mechanistic insights into AD, focusing on epigenetic alterations and the involvement of FA in AD development. The exploration of chemical exposures as contributing factors to AD may provide new insights into AD mechanisms and could identify potential novel therapeutic targets.

Formaldehyde induces ferritinophagy to damage hippocampal neuronal cells

“…Although the wide application of FA has been approved by various industries, its toxicity cannot be disregarded, especially neurotoxicity. FA-induced neurotoxicity is one of the risk factors for neurodegenerative diseases (Tulpule and Dringen, 2013;Wang et al, 2019). Nevertheless, the mechanism of FAinduced neurotoxicity is still unclear and needs further exploration.…”

Influence of Woodsmoke Exposure on Molecular Mechanisms Underlying Alzheimer’s Disease: Existing Literature and Gaps in Our Understanding

“…Several reviews have been conducted which explore the potential for environmental effect on epigenetic patterns to modify disease pathogenesis, including AD. [11][12][13][14][15][16][17] Additionally, reviews have been conducted which explore the association between AAP exposure and onset of AD or dementia. [18][19][20][21][22][23] Very recently, a review has assessed the effects of exposure to bushfire smoke on brain health.…”

“…More work is needed to characterize the ability of TWS constituents, individually or as a whole, to influence epigenetics mechanisms that underlie AD though recent publications have suggested the plausibility of this relationship. Specifically, Wang et al 13 postulates that epigenetic modifications might help to explain the link between formaldehyde (a component of TWS) exposure and subsequent onset of AD.…”

Mechanistic Investigation on Chemiluminescent Formaldehyde Probes

“…Formaldehyde (FA) is a common environmental pollutant. Inhaling excessive FA can damage the human nervous system, affect the memory, cognition, and learning ability, and increase the risk of neurodegenerative diseases such as Alzheimer's disease [1] . Environmental FA mainly originates from human activities such as burning coal and natural gas [2] .…”