Alzheimer's Disease and Methanol Toxicity (Part 1): Chronic Methanol Feeding Led to Memory Impairments and Tau Hyperphosphorylation in Mice

Abstract

Although methanol toxicity is well known for acute neurological sequelae leading to blindness or death, there is a new impetus to investigate the chronic effects of methanol exposure. These include a recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology. In the present study, mice were fed with methanol to revisit the chronic effects of methanol toxicity, especially as it pertains to AD progression. Three groups of mice (n = 9) were given either water as a control or a methanol solution (concentrations of 2% or 3.8%) over a 6-week period. The methanol-fed mice were found to have impaired spatial recognition and olfactory memory in Y-maze and olfactory memory paradigms. Immunohistochemical analysis of the mouse brains found increased neuronal tau phosphorylation in the hippocampus and an increased cellular apoptotic marker in hippocampal CA1 neurons (~10% of neurons displayed chromatin condensation) in the methanol-fed groups. Two additional in vitro experiments in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells found that formaldehyde, but not methanol or the methanol end product formic acid, induced microtubule disintegration and tau protein hyperphosphorylation. The findings of the behavioral tests and immunohistochemical analysis suggested that the methanol-fed mice presented with partial AD-like symptoms. The in vitro experiments suggested that formaldehyde was most likely the detrimental component of methanol toxicity related to hippocampal tau phosphorylation and the subsequent impaired memory in the mice. These findings add to a growing body of evidence that links formaldehyde to AD pathology.

Metabolic Methanol: Molecular Pathways and Physiological Roles

“…The metabolism of methanol and formaldehyde in brain cells is important for the function of this vital organ (472). Moreover, the elevation of brain formaldehyde levels is likely to result in neurodegenerative diseases (386,448,450,463,464,517,518). Methanol and the products of its metabolism in brain cells may be synthesized in situ or be introduced from peripheral organs via the bloodstream by overcoming the blood-brain barrier.…”

Advance of sporadic Alzheimer's disease animal models

“…164 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. 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.…”

A Sensitive and Rapid Method for Detecting Formaldehyde in Brain Tissues

“…During aging, chronic accumulation of endogenous FA is thought to be a risk factor for sporadic age-related dementia [10, 28]. Furthermore, excess FA has been found to contribute to the pathological aggregation of amyloid fragments and tau hyperphosphorylation in normal adult mice and monkeys [29, 30]. More importantly, a direct intracerebroventricular injection of excess FA into animal models causes memory decline [13–15].…”