Formaldehyde as a trigger for protein aggregation and potential target for mitigation of age-related, progressive cognitive impairment

Abstract

Recently, formaldehyde (FA), existing in a number of different cells including neural cells, was found to affect age-related cognitive impairment. Oral administration of methanol (the metabolic precursor of FA) triggers formation of senile plaques (SPs) and Tau hyperphosphorylation in the brains of monkeys with memory decline. Intraperitoneal injection of FA leads to hyperphosphorylation of Tau in wild-type mouse brains and N2a cells through activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, formaldehyde at low concentrations can directly induce Tau aggregation and amyloid β (Aβ) peptide deposits in vitro. Formaldehyde-induced Tau aggregation is implicated in cytotoxicity and neural cell apoptosis. Clarifying how FA triggers Aβ deposits and Tau hyperphosphorlyation will not only improve our understanding of the molecular and cellular mechanisms of age-related cognitive impairment but will also contribute to the ongoing investigation of alternate targets for new drugs. Here, we review the role of FA, particularly that of endogenous origin, in protein aggregation and as a potential drug intervention in the development of agerelated cognitive impairment.

Early multidomain intervention to stave off Alzheimer’s disease

“…因此Hu等人 [16] 认为, 导致AD的环境因素远比遗传因 素重要. 人类代谢失调疾病的发生具有一个基本特 性, 即年龄越小所患的疾病越与遗传因素相关; 年龄 越高发生的疾病, 越与内外环境因素相关(图2) [17] .…”

“…Tong等人 [24] 发现, 随着年龄增加, 体内甲醛的 含量也增加; Qiang等人 [25] 观察到, 小鼠在衰老过程 中, 内源甲醛代谢失调的原因是: 产生甲醛的敏感性 图 2 (网络版彩色)代谢性疾病的发生与基因和环境之间的关系. 越 是幼年时期发生的疾病, 越与遗传因素相关; 越是老年时期发生的 疾病, 越与内外环境因素相关 [17] 酶活性增加, 而降解甲醛的乙醇脱氢酶3(alcohol dehydrogenase III, ADH3)活力下降. 临床检验显示, AD 病人体内的甲醛浓度显著高于正常对照, 体内甲醛浓 度 与 认 知 损 伤 程 度 呈 正 相 关 [26] .…”

Cerebrospinal Fluid Aβ42 Levels: When Physiological Become Pathological State

“…Notably, recent experimental findings demonstrated that other mechanisms independent from A β could be responsible for cognitive decline of AD. In particular, it has been proposed that inducing hyperphosphorylation of tau could be involved in mechanisms of neurodegeneration . Unexpectedly, other substances like formaldehyde or mechanisms of D‐ribosylation, not involved in A β metabolism could trigger neuronal degeneration.…”

Brain Formaldehyde is Related to Water Intake behavior

“…However, the inducers that are involved in chronic dehydration require further attention. Recently, formaldehyde (FA), which is present in all human cells including neural cells, was found to affect age-related cognitive impairment [ 12 , 13 , 14 ]. The levels of uric FA are positively related to the severity of cognitive impairment in clinical AD patients [ 15 ].…”

“…Furthermore, FA also affects the emotional behaviors of animals, including depression and anxiety [ 21 , 22 ]. Although the relationship between FA and brain dysfunction has been intensively studied [ 23 , 24 ], the effects of formaldehyde on water intake behavior and dehydration have not been investigated to date.…”