Clemastine attenuates AD-like pathology in an AD model mouse via enhancing mTOR-mediated autophagy

Zhen-Yu Li; Li-Hua Chen; Xiu-Yun Zhao; Hong Chen; Yan-Yun Sun; Mei-Hong Lu; Zhao-Tao Wang; Mei Chen; Li Lu; Wenhui Huang; Rui Chen; De-En Xu; Ru-Xiang Xu; Quan-Hong Ma

doi:10.1016/j.expneurol.2021.113742

Clemastine attenuates AD-like pathology in an AD model mouse via enhancing mTOR-mediated autophagy

Exp Neurol. 2021 Aug:342:113742. doi: 10.1016/j.expneurol.2021.113742. Epub 2021 May 6.

Authors

Zhen-Yu Li¹, Li-Hua Chen², Xiu-Yun Zhao³, Hong Chen³, Yan-Yun Sun³, Mei-Hong Lu³, Zhao-Tao Wang⁴, Mei Chen⁵, Li Lu⁶, Wenhui Huang⁷, Rui Chen⁸, De-En Xu⁹, Ru-Xiang Xu¹⁰, Quan-Hong Ma¹¹

Affiliations

¹ Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province 215021, China; Department of Neurosurgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
² Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.
³ Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province 215021, China.
⁴ Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province 215021, China.
⁵ Institute of Health and Disease, Binzhou Medical University, Yantai, Shandong province 264003, China.
⁶ Department of Anatomy, Shanxi Medical University, Taiyuan 030001, China.
⁷ Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, D-66421 Homburg, Germany.
⁸ Department of Respiratory Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215000, China.
⁹ Wuxi No. 2 People's Hospital, Wuxi, Jiangsu Province 214000, China. Electronic address: xudeen@njmu.edu.cn.
¹⁰ Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China. Electronic address: xuruxiang1123@uestc.edu.cn.
¹¹ Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province 215021, China. Electronic address: maquanhong@suda.edu.cn.

PMID: 33965410
DOI: 10.1016/j.expneurol.2021.113742

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with limited available drugs for treatment. Enhancing autophagy attenuates AD pathology in various AD model mice. Thus, development of potential drugs which enhance autophagy may bring beneficial effects in AD therapy. In the present study, we show clemastine, a first-generation histamine H1R antagonist and being originally marketed for the treatment of allergic rhinitis, ameliorates AD pathogenesis in APP/PS1 transgenic mice. Chronic treatment with clemastine orally reduced amyloid-β (Aβ) load, neuroinflammation and cognitive deficits of APP/PS1 transgenic mice. Clemastine decreases Aβ generation via reducing the levels of BACE1, CTFs of APP. Mechanistically, clemastine enhances autophagy concomitant with a suppression of mTOR signaling. Therefore, we propose that clemastine attenuates AD pathology via enhancing mTOR-mediated autophagy.

Keywords: Alzheimer's disease; Autophagy; Clemastine; Neurodegenerative disease; mTOR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Alzheimer Disease / pathology*
Alzheimer Disease / prevention & control*
Amyloid beta-Protein Precursor / genetics
Animals
Autophagy / drug effects*
Autophagy / physiology
Clemastine / pharmacology
Clemastine / therapeutic use*
Dose-Response Relationship, Drug
HeLa Cells
Histamine H1 Antagonists / pharmacology
Histamine H1 Antagonists / therapeutic use
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Presenilin-1
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Amyloid beta-Protein Precursor
Histamine H1 Antagonists
Presenilin-1
Clemastine
mTOR protein, mouse
TOR Serine-Threonine Kinases