Zhang Wei, Xu Chengchao, Sun Jichao, Shen Han-Ming, Wang Jigang, Yang Chuanbin
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.
Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.
Acta Pharm Sin B. 2022 Mar;12(3):1019-1040. doi: 10.1016/j.apsb.2022.01.008. Epub 2022 Jan 21.
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 (A) 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 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, A 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.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征为记忆丧失和认知功能障碍。神经元细胞中包括β淀粉样蛋白（A）肽和微管相关蛋白tau（MAPT/tau）在内的错误折叠蛋白聚集体的积累是AD的标志。到目前为止，AD病因的确切潜在机制尚未完全明确，且AD的有效治疗方法有限。自噬是一种进化上保守的细胞分解代谢过程，通过该过程受损的细胞器和蛋白聚集体被溶酶体降解。最近，越来越多的证据表明自噬 - 溶酶体途径的损伤与AD发病机制有关。有趣的是，增强自噬以清除蛋白聚集体已被提出作为AD的一种有前景的治疗策略。在此，我们首先总结最近关于AD中自噬 - 溶酶体途径损伤的遗传学、病理学和实验研究。然后我们描述AD中自噬 - 溶酶体途径与两种病理蛋白A和MAPT/tau之间的相互作用。最后，我们讨论在动物模型和临床试验中针对自噬 - 溶酶体途径进行AD治疗的潜在治疗策略和小分子。总体而言，本文强调了自噬 - 溶酶体途径在AD发病机制中的关键作用以及自噬 - 溶酶体途径中潜在的可药物靶向治疗AD的靶点。
