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Chronic methanol exposure induces cognitive impairment and Alzheimer's-like pathology in rhesus monkeys
Hongwei Li1, Changhua Shi1, Keya Li1
1National 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.
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 recapitulate 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 impairment without significant motor or visual deficits. Neuropathology revealed brain atrophy, 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 formaldehyde, 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 sporadic 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.
Insights
Chronic methanol exposure in monkeys caused cognitive decline and Alzheimer
Area of Science:
- Neuroscience and Toxicology
- Primate Models for Neurodegenerative Diseases
Background:
- Lack of effective animal models for sporadic Alzheimer's disease (AD) hinders therapeutic development.
- Endogenous formaldehyde, a byproduct of methanol metabolism, is a neurotoxic agent linked to cognitive decline.
Purpose of the Study:
- To investigate if chronic, low-dose methanol exposure can induce AD-like pathology and cognitive deficits in rhesus monkeys.
- To establish a nonhuman primate model for sporadic AD using an environmental-metabolic insult.
Main Methods:
- Adult rhesus monkeys were exposed to low-concentration methanol for nine months.
- Behavioral tests assessed cognition, locomotion, sleep, and vision.
- Postmortem analyses included histopathology, immunohistochemistry, immunofluorescence, and Western blot to evaluate neuropathology and molecular markers of AD and cellular stress.
Main Results:
- Methanol exposure resulted in progressive cognitive and memory impairment, with no significant motor or visual deficits.
- Neuropathology showed brain atrophy, neuronal loss, synaptic damage, microglial activation, and mitochondrial disorganization.
- Exposed animals displayed hallmark AD-like changes: increased amyloid-β deposition, tau hyperphosphorylation, and TDP-43 dysregulation, linked to elevated formaldehyde, mitochondrial fission, autophagy, and apoptosis.
Conclusions:
- Chronic low-dose methanol exposure in rhesus monkeys effectively replicates cognitive deficits and neuropathological features of sporadic Alzheimer's disease.
- This formaldehyde-toxicity-driven model offers a reproducible and translationally relevant nonhuman primate model for AD research and therapeutic evaluation.
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