Part 1: Methanol feeding lead to AD like tauopathy in mice Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing age-related dementia. It is associated with genetic factors leading to amyloid plaque formation and neurofibillary tangles within the brain. A proper animal model is important for Alzheimer's disease (AD) research. Recent studies have established a link between the metabolite formaldehyde (FA) and AD pathologies, including one of the AD's most important characteristics - Tau hyperphosphorylation. In the present study, mice were fed with methanol as a FA precursor to develop a new AD animal model. Three groups of mice (N = 9) were given either water as a control or a methanol solution (concentrations of 2% and 3.8%) for a six week period. AD-dementia like symptoms were confirmed in the mice with Y-maze and olfactory memory tests in order to assess spatial recognition and olfactory memory, respectively. Then tau hyperphosphorylation, amyloid plague formation and neuronal apoptosis of hippocampus CA1 were measured in the mouse brains. In contrast to the control group, the methanol-fed groups were found to have a level of memory impairment; they failed to recognize the novel arm in the Y-maze apparatus and failed to establish recognition of a lemon odor in the olfactory test. Immunohistochemistry experiments found increased neuronal Tau phosphorylation in the hippocampus and increased cellular apoptotic markers in hippocampal CA1 neurons (approx. 10% of neurons displayed chromatin condensation) in the methanol-fed groups, but were unable to find changes in amyloid-plaque formation. Two additional in vitro experiments were performed in mouse embryonic cerebral cortical neurons and N2a cells to evalutate which methanol metabolite caused AD associated changes (e.g. tau phosphorylation). The in vitro investigations found that FA, not methanol nor formic acid, significantly induced microtubule disintegration and Tau protein hyperphosphorylation. All told, the behavioral tests, immunohistochemical analysis, and in vitro experiments indicated the FA impaired memory through hippocampal related tau-phosphorylation. Furthermore, these findings suggested that the methanol-fed mouse model developed here is a new AD animal model based on tauopathies, especially in the Tau-hyperphosphorylation dependent loss of microtubules in tangle formation. Keywords: methanol, formaldehyde, Alzheimer's disease, cognitive impairment, Tau hyperphosphorylation. Part 2: Methanol feeding lead to AD model in monkeys Four monkeys (N = 4) were fed with methanol solution (dose 2 ml/kg, concentration: 3% diluted in water) over a one month period. To confirm AD-dementia like symptoms in the monkeys, variable spatial delayed tasks (VSTD) were used to determine whether the working memory was impaired in each monkey before and after the chemical feed. Then, Aβdeposits were measured in the monkeys’ brains post-mortem as well as the Tau hyperphosphorylation in the CSF (Cerebral Spinal Fluid). The monkeys failed to remember which side of the apparatus contained the food reward during the variable spatial delayed tasks （VSTD） after the methanol-feeding regimen in contrast to the baseline before the methanol-feeding. The monkeys were also found to have a similar correct response rate as that found immediately following the methanol-feeding regimen after a 3 month or a half year recovery period. This indicated that the level of memory impairment was stable over an extended period. Furthermore, immunohistochemistry found increased neuronal Tau phosphorylation in the CSF and Aβdeposits as well as tau phosphorylation in the monkeys’ brains. The findings in the behavior tests that monkeys given methanol had dysfunctional working memory as well as the findings of Aβdeposits and tau phosphorylation in the brain sections and CSF Tau phosphorylation suggested that the methanol-fed monkey model developed here is a new AD-like animal mo
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