Kim Yeji, Ha Tae-Young, Lee Myung-Shik, Chang Keun-A
Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences & Technology, Gachon University, Incheon 21999, Korea.
Department of Pharmacology, College of Medicine, Gachon University, Incheon 21999, Korea.
Int J Biol Sci. 2025 Jan 13;21(3):1014-1031. doi: 10.7150/ijbs.103028. eCollection 2025.
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) formed from hyperphosphorylated Tau, and widespread neuronal loss. The autophagy-lysosomal pathway plays a crucial role in maintaining cellular homeostasis by degrading and recycling of damaged organelles and aggregate amyloid proteins implicated in AD. Lysosomes are key effectors of autophagic process, responsible for the breakdown of a variety of damaged organelles and aggregate or dysfunctional proteins. This review examines the role of lysosomal dysfunction in AD pathophysiology, focusing on genetic factors, acidification abnormalities, and other contributing factors. We also explore the involvement of lysosomal dysfunction of microglia in AD pathology, and cover the role of lysosomal stress response (LSR) in cellular response to neuronal injury associated with AD. Furthermore, we discuss potential therapeutic strategies targeting lysosomal proteolysis pathway and addressing lysosomal dysfunction for AD treatment, including the pharmacologically activating lysosomal activity, regulating TFEB, and considering other emerging approaches.
阿尔茨海默病（AD）的特征是β淀粉样蛋白（Aβ）斑块的积累、由过度磷酸化的 Tau 形成的神经原纤维缠结（NFTs）以及广泛的神经元丢失。自噬-溶酶体途径通过降解和循环受损细胞器以及与 AD 相关的聚集淀粉样蛋白，在维持细胞内稳态中发挥关键作用。溶酶体是自噬过程的关键效应器，负责分解各种受损细胞器以及聚集或功能失调的蛋白质。本综述探讨了溶酶体功能障碍在 AD 病理生理学中的作用，重点关注遗传因素、酸化异常和其他促成因素。我们还探讨了小胶质细胞溶酶体功能障碍在 AD 病理学中的参与情况，并涵盖了溶酶体应激反应（LSR）在细胞对与 AD 相关的神经元损伤的反应中的作用。此外，我们讨论了针对溶酶体蛋白水解途径和解决溶酶体功能障碍以治疗 AD 的潜在治疗策略，包括药理学激活溶酶体活性、调节转录因子 EB（TFEB）以及考虑其他新兴方法。
