Alzheimer's disease and methanol toxicity (Part 1): Chronic methanol feeding led to memory impairments and tau hyperphosphorylation in mice

Meifeng Yang, Jing Lu, Junye Miao, Joshua Rizak, Jianzhen Yang, Rongwei Zhai, Jun Zhou, Jiagui Qu, Jianhong Wang, Shangchuan Yang, Yuanye Ma, Xintian Hu, Rongqiao He

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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.

Original languageEnglish
Pages (from-to)1117-1129
Number of pages13
JournalJournal of Alzheimer's Disease
Issue number4
Publication statusPublished - 25 Jul 2014
Externally publishedYes


  • Alzheimer's disease
  • cognitive impairment
  • disease progression
  • formaldehyde
  • methanol
  • tau hyperphosphorylation

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