Regulatory Mechanisms and Therapeutic Implications of Lysosomal Dysfunction in Alzheimer’s Disease

Abstract

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.