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Alzheimer's disease and methanol toxicity (part 2): lessons from four rhesus macaques (Macaca mulatta) chronically
Meifeng Yang1, Junye Miao2, Joshua Rizak1
1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, P.R. China University of the Chinese Academy of Sciences, Beijing, P.R. China.
Abstract:
A recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology has provided a new impetus to investigate the chronic effects of methanol exposure. This paper expands this investigation to the non-human primate, rhesus macaque, through the chronic feeding of young male monkeys with 3% methanol ad libitum. Variable Spatial Delay Response Tasks of the monkeys found that the methanol feeding led to persistent memory decline in the monkeys that lasted 6 months beyond the feeding regimen. This change coincided with increases in tau protein phosphorylation at residues T181 and S396 in cerebrospinal fluid during feeding as well as with increases in tau phosphorylated aggregates and amyloid plaques in four brain regions postmortem: the frontal lobe, parietal lobe, temporal lobe, and the hippocampus. Tau phosphorylation in cerebrospinal fluid was found to be dependent on methanol feeding status, but phosphorylation changes in the brain were found to be persistent 6 months after the methanol feeding stopped. This suggested the methanol feeding caused long-lasting and persistent pathological changes that were related to AD development in the monkey. Most notably, the presence of amyloid plaque formations in the monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defenses in mice against methanol toxicity may have limited previous investigations into AD pathology. Nonetheless, these findings support a growing body of evidence that links methanol and its metabolite formaldehyde to AD pathology.
Insights
Chronic methanol exposure in rhesus macaques caused persistent memory decline and Alzheimer
Area of Science:
- Neuroscience
- Toxicology
- Pathology
Background:
- Emerging evidence links formaldehyde, a methanol metabolite, to Alzheimer's disease (AD) pathology.
- Previous animal models may have limitations due to species-specific methanol metabolism.
Purpose of the Study:
- To investigate the chronic effects of methanol exposure on non-human primates.
- To assess the development of AD-related pathology following methanol ingestion.
Main Methods:
- Rhesus macaques were chronically fed 3% methanol.
- Cognitive function was assessed using Variable Spatial Delay Response Tasks.
- Cerebrospinal fluid and brain tissue were analyzed for tau phosphorylation and amyloid plaques postmortem.
Main Results:
- Methanol feeding induced persistent memory decline lasting over 6 months.
- Increased tau phosphorylation at T181 and S396 in cerebrospinal fluid was observed during feeding.
- Postmortem analysis revealed tau aggregates and amyloid plaques in multiple brain regions.
Conclusions:
- Chronic methanol exposure in non-human primates replicates key pathological features of Alzheimer's disease.
- Amyloid plaque formation in macaques suggests this model is more relevant for AD research than traditional mouse models.
- Findings support a causal link between methanol/formaldehyde and AD pathology, highlighting potential environmental risk factors.
