DOI: 10.1002/ame2.70142
Chronic methanol exposure induces cognitive impairment and Alzheimer's-like pathology in rhesus monkeys
Hongwei Li
Changhua Shi
Keya Li
Xinjing Fu
Ying Lyu
Yanfeng Xu
Yunlin Han
Wei Liang
Qin Chuan
Ling Zhang
National Human Diseases Animal Model Resource Center,NHC Key Laboratory of Human Disease Comparative Medicine,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases,National Center of Technology Innovation for Animal Model,Chinese Academy of Medical Sciences(CAMS),Peking Union Medical College(PUMC),Beijing,China
摘要：Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agent linked to cognitive decline,this study investigated whether chronic,low-dose methanol exposure could recapitu-late AD-like pathology and cognitive deficits in rhesus monkey,thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult.
Methods:Adult rhesus monkeys received low-concentration methanol for 9 months.Behavioral tests for cognition,locomotion,sleep,and vision were conducted.Postmortem analyses involved histopathological examination,immunohistochemistry,immunofluorescence,and Western blot to evaluate neuronal integrity,microglial activation,and the expression of key proteins associated with AD(amyloid-β[Aβ],phosphorylated tau,TAR DNA-binding protein 43[TDP-43])and cellular stress(synaptic markers,mitochondrial fission,autophagy,and apoptosis-related proteins).
Results:Chronic methanol exposure led to progressive cognitive and memory impair-ment without significant motor or visual deficits.Neuropathology revealed brain atro-phy,neuronal loss,synaptic damage,microglial activation,and mitochondrial structural disorganization.Critically,the exposed animals exhibited hallmark AD-like molecular alterations,including increased Aβ deposition,tau hyperphosphorylation,and TDP-43 dysregulation.Furthermore,neurotoxicity was associated with elevated urinary formal-dehyde,enhanced mitochondrial fission,increased autophagy,and elevated apoptosis.
Conclusion:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features.This model,driven by endogenous formaldehyde toxicity,effectively mimics key aspects of spo-radic AD.Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.
机标关键词：alzheimerexposurecognitivemethanolchronicimpairmentinducesmonkeys
论文发表日期：2026-02-28
在线出版日期：2026-03-31（本平台首次上网日期，不代表文献的发表时间）
页数：16( 264-279 )
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