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Research Paper|Volume 11, Issue 19|pp 8642—8663

Decreased levels of circulating trimethylamine N-oxide alleviate cognitive and pathological deterioration in transgenic mice: a potential therapeutic approach for Alzheimer’s disease

Qiang Gao1, Yuan Wang1, Xin Wang2, Shuang Fu2, Xin Zhang2, Rui-Tao Wang2, Xin Zhang3
  • 1Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
  • 2Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, China
  • 3Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
* Co-first authors, equal contribution
Received: July 5, 2019Accepted: September 27, 2019Published: October 14, 2019
https://doi.org/10.18632/aging.102352

Copyright © 2019 Gao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has been implicated in the pathogenesis of Alzheimer’s disease (AD). However, the mechanisms by which TMAO influence cognitive and pathological processes in the AD have not been investigated. In this study, we found that the circulating TMAO levels displayed an age-related increase in both WT and APP/PS1 mice and association with AD-like behavioral and pathological profile. Reduced TMAO by 3,3-Dimethyl-1-butanol (DMB) treatment ameliorated the cognitive deterioration and long-term potentiation (LTP) in APP/PS1 mice. Moreover, DMB treatment also induced a decrease in the Amyloid-β (Aβ)1-42, β-secretase, and β-secretase-cleaved C-terminal fragment (βCTF) levels in the hippocampus. Finally, the effects obtained after treatment with DMB were accompanied by a reduction in circulating clusterin levels and hippocampal neuroinflammatory status in APP/PS1 mice. These findings demonstrate that elevated circulating TMAO during the aging process might deteriorate cognitive function and pathology in APP/PS1 mice.