Research Paper Volume 12, Issue 1 pp 628—649

Concomitant memantine and Lactobacillus plantarum treatment attenuates cognitive impairments in APP/PS1 mice

Qiu-Jun Wang 1, *, , Yue-E Shen 2, *, , Xin Wang 3, , Shuang Fu 3, , Xin Zhang 3, , Yi-Na Zhang 4, , Rui-Tao Wang 3, ,

  • 1 General Practice Department, The Second Affiliated Hospital, Harbin Medical University, Harbin 150086, China
  • 2 Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
  • 3 Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, China
  • 4 Department of Geriatrics, The Second Affiliated Hospital, Harbin Medical University, Harbin 150086, China
* Equal contribution

received: November 6, 2019 ; accepted: December 23, 2019 ; published: January 6, 2020 ;

https://doi.org/10.18632/aging.102645
How to Cite

Copyright © 2020 Wang 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) is a gut microbial metabolite that promotes Alzheimer’s disease (AD) progression. Given that probiotics can alleviate AD symptoms by inhibiting the synthesis of TMAO, here we investigated the correlation between TMAO and cognitive deterioration by measuring TMAO levels in the plasma of choline-treated APP/PS1 mice (an AD mouse model) with and without probiotic treatments. We found that declines in L. plantarum in the gut were associated with cognitive impairment. Moreover, 12-weeks of treatment with memantine plus L. plantarum ameliorated cognitive deterioration, decreased Αβ levels in the hippocampus, and protected neuronal integrity and plasticity. These effects were accompanied by reductions in TMAO synthesis and neuroinflammation. These experiments demonstrate that L. plantarum augments the beneficial therapeutic effects of memantine treatment in APP/PS1 mice by remodeling the intestinal microbiota, inhibiting the synthesis of TMAO, and reducing clusterin levels. Our results thus highlight intestinal microbiota as a potential therapeutic target to decrease the risk of AD.

Abbreviations

AD: Alzheimer’s disease; ANOVA: One-way analysis of variance; APP: Amyloid precursor protein; AUC: Area under the curve; Aβ: Amyloid-β; L. plantarum: Lactobacillus plantarum; FMOs: Flavin monooxygenases; G-CSF: Granulocyte colony-stimulating factor; GM-CSF: Granulocyte-macrophage colony-stimulating factor; IFNγ: Interferon-γ; IL: Interleukin; IP: Interferon-induced protein; LTP: Long-term potentiation; MCP-1: Monocyte chemotactic protein-1; MIP-1β: Macrophage inflammatory protein-1β; PC: Principal components; PCA: Principal component analysis; RANTES: Regulated upon activation normal T cell expressed and secreted factor; ROC: Receiver operating characteristic; TMA: Trimethylamine; TMAO: Trimethylamine-N-oxide; TNF: Tumor necrosis factor; WT: Wild type.