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Wei Zhang, Chengchao Xu, Jichao Sun, Han-Ming Shen, Jigang Wang, Chuanbin Yang. Impairment of the autophagy-lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1019-1040

Impairment of the autophagy-lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential
Wei Zhanga,b, Chengchao Xua,c, Jichao Suna, Han-Ming Shend, Jigang Wanga,c,e, Chuanbin Yanga
a. Department of Geriatrics, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China;
b. Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China;
c. Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China;
d. Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China;
e. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Abstract:
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD. We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.
Key words:    Alzheimer's disease (AD)    Amyloid beta (Aβ) peptides    MAPT/tau    Autophagy-lysosomal pathway    Autophagy enhancers    Autophagy    Mitophagy    Neurodegenerative diseases   
Received: 2021-09-21     Revised: 2021-11-09
DOI: 10.1016/j.apsb.2022.01.008
Funds: We apologize to colleagues whose work could not be cited due to space limitations. We acknowledge the funding supports from the National Natural Science Foundation of China (82003721, 82071193, 32170774 and 32000673), Shenzhen Science and Technology Innovation Commission (JCYJ20210324114014039, China), China Postdoctoral Science Foundation (2020M683182), and Guangdong Basic and Applied Basic Research Foundation (2020A1515110549, China).
Corresponding author: Han-Ming Shen,E-mai:hmshen@um.edu.mo;Jigang Wang,E-mai:jgwang@icmm.ac.cn;Chuanbin Yang,E-mai:nkyangchb@gmail.com     Email:hmshen@um.edu.mo;jgwang@icmm.ac.cn;nkyangchb@gmail.com
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Wei Zhang
Chengchao Xu
Jichao Sun
Han-Ming Shen
Jigang Wang
Chuanbin Yang

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