Alzheimer's Disease-Like Pathologies and Cognitive Impairments Induced by Formaldehyde in Non-Human Primates

Zhai, Runsheng; Rizak, Joshua D.; Zheng, Na; He, Xiaping; Li, Zhenhui; Yin, Yan; Su, Tao; He, Yingge; He, Rong; Ma, Yuanye; Yang, Meifeng; Wang, Zhengbo; Hu, Xintian

doi:10.2174/1567205015666180904150118

Cited by 29 publications

(28 citation statements)

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“…In rodent studies, elevated FA can lead to memory impairment, Tau protein hyperphosphorylation, and neuronal loss; rodent animal models of AD also show an imbalance in FA metabolism and elevated FA in vivo ( Qiang et al, 2014 ; Tong et al, 2013 ; Yang et al, 2014a ). In non-human primate (NHP) studies, elevated FA levels not only lead to impaired memory, but also to the occurrence of all the pathological hallmarks of human AD in the brain, including senile plaques, neurofibrillary tangles, neuronal loss, and glial proliferation ( Yang et al, 2014b ; Zhai et al, 2018 ). Studies have shown that very low concentrations of FA can promote the aggregation of Aβ and the formation of structures similar to senile plaques in vitro ( Chen et al, 2006 ; Rizak et al, 2014 ).…”

Section: Dear Editormentioning

confidence: 99%

Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys

Li¹,

He²,

Li³

et al. 2020

Zoological Research

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A: Intergroup analyses of Aβ 40 concentrations. B: Intergroup analyses of Aβ 42 concentrations. C: Intergroup analyses of FA concentrations. D: Correlation between CSF Aβ 40 and FA concentrations in young group ( R =–0.3385, P =0.2172). E: Correlation between CSF Aβ 40 and FA concentrations in middle-aged group ( R =0.02914, P =0.8976). F: Correlation between CSF Aβ 40 and FA concentrations in aged group ( R =–0.5318, P =0.0158). G: Correlation between CSF Aβ 42 and FA concentrations in young group ( R =–0.379, P =0.1635). H: Correlation between CSF Aβ 42 and FA concentrations in middle-aged group ( R =0.4296, P =0.046). I: Correlation between CSF Aβ 42 and FA concentrations in aged group ( R =–0.5344, P =0.0184). Error bars indicate mean± standard deviation ( SD ). *: P <0.05, **: P <0.01, ***: P <0.001. Aβ: β-amyloid; CSF: Cerebrospinal fluid.

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Section: Dear Editormentioning

confidence: 99%

Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys

Li¹,

He²,

Li³

et al. 2020

Zoological Research

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“…In addition, they found formaldehyde, rather than methanol or the methanol end product formic acid, led to Tau hyperphosphorylation in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells . The same group also reported that spatial working memory impairments, increased Tau phosphorylation and neuronal loss, accompanied by the presence of Aβ + neuritic‐like plaques and NFT‐like formations were observed in the brain from young rhesus macaques (5‐8 years old) intracerebroventricularly injected formaldehyde for 12 months …”

Section: Nhps: a Bridge Between Rodents And Humans?mentioning

confidence: 95%

“…165 The same group also reported that spatial working memory impairments, increased Tau phosphorylation and neuronal loss, accompanied by the presence of Aβ + neuritic-like plaques and NFT-like formations were observed in the brain from young rhesus macaques (5-8 years old) intracerebroventricularly injected formaldehyde for 12 months. 166 Given that the brains of humans and NHPs have considerable similarities in their overall architecture and functional network organization, the NHPs AD model is likely to greatly improve our understanding of the pathogenesis of AD and bring about effective development of therapeutics. However, the use of NHPs in most laboratories is extremely limited due to the high prices, high feeding costs, long experimental cycles and ethical considerations.…”

Section: Nhps: a Bridge Between Rodents And Humans?mentioning

confidence: 99%

Advance of sporadic Alzheimer's disease animal models

Zhang

Chen

Mak

et al. 2019

Medicinal Research Reviews

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Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disease. In the past decades, numbers of promising drug candidates showed significant anti‐AD effects in preclinical studies but failed in clinical trials. One of the major reasons might be the limitation of appropriate animal models for evaluating anti‐AD drugs. More than 95% of AD cases are sporadic AD (sAD). However, the anti‐AD drug candidates were mainly tested in the familial AD (fAD) animal models. The diversity between the sAD and fAD might lead to a high failure rate during the development of anti‐AD drugs. Therefore, an ideal sAD animal model is urgently needed for the development of anti‐AD drugs. Here, we summarized the available sAD animal models, including their methodology, pathologic features, and potential underlying mechanisms. The limitations of these sAD animal models and future trends in the field were also discussed.

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“…The spatial working memory ability of the FA group was found to be remarkably decreased after 2 months of treatment, and the notable presence of AD pathological markers was observed in memory-related brain regions of FA-treated monkeys after 12 months of administration. 94 FA-induced AD-like features in primate brain suggest that FA may play an important role in AD pathogenesis.…”

Section: Formaldehyde and Alzheimer's Diseasementioning

confidence: 98%

“…93 Moreover, Zhai et al reported that FA induces AD-like pathologies and cognitive impairments in rhesus monkeys. 94 Monkeys without AD-related mutations in the APP, PSEN1, and PSEN2 genes were chronically exposed to FA by intracerebroventricular injections over a 1 year period. The spatial working memory ability of the FA group was found to be remarkably decreased after 2 months of treatment, and the notable presence of AD pathological markers was observed in memory-related brain regions of FA-treated monkeys after 12 months of administration.…”

Section: Formaldehyde and Alzheimer's Diseasementioning

confidence: 99%

Formaldehyde, Epigenetics, and Alzheimer’s Disease

Wang

Chen

et al. 2019

Chem. Res. Toxicol.

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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.

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Alzheimer's Disease-Like Pathologies and Cognitive Impairments Induced by Formaldehyde in Non-Human Primates

Abstract: FA was found to induce major AD-like pathological markers and cognitive impairments in young rhesus monkeys independent of genetic predispositions. This suggests FA may play a significant role in the initiation and progression of the disease.

Cited by 29 publications

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Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys

Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys

Advance of sporadic Alzheimer's disease animal models

Formaldehyde, Epigenetics, and Alzheimer’s Disease

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