Alzheimer's Disease and Methanol Toxicity (Part 2): Lessons from Four Rhesus Macaques (Macaca mulatta) Chronically Fed Methanol

Article type: Research Article

Authors: Yang, Meifeng^{a; e; 1} | Miao, Junye^{b; e; 1} | Rizak, Joshua^{a; e; 1} | Zhai, Rongwei^{a; e} | Wang, Zhengbo^a | Huma, Tanzeel^a | Li, Ting^{b; e} | Zheng, Na^{a; e} | Wu, Shihao^{a; e} | Zheng, Yingwei^a | Fan, Xiaona^a | Yang, Jianzhen^a | Wang, Jianhong^a | Yang, Shangchuan^a | Ma, Yuanye^{a; b; d} | Lü, Longbao^c | He, Rongqiao^{b; *} | Hu, Xintian^{a; c; *}

Affiliations: [a] Key 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 | [b] State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China | [c] Kunming Primate Research Center of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, P.R. China | [d] Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan, China | [e] University of the Chinese Academy of Sciences, Beijing, P.R. China

Correspondence: [*] Correspondence to: Xintian Hu, State Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, P.R. China. Tel.: +0086 871 5197002; Fax: +0086 871 5197002; E-mail: [email protected] (Xintian Hu) and Rongqiao He, Tel.: +0086 10 64889876; Fax: +0086 10 64853625; E-mail: [email protected] (Rongqiao He).

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer's disease, amyloid plaque formation, cognitive impairment, disease progression, formaldehyde, methanol toxicity, tau hyperphosphorylation

DOI: 10.3233/JAD-131532

Journal: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1131-1147, 2014