Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by two core pathological features: senile plaques formed by amyloid-β protein (Aβ) deposits and neurofibrillary tangles formed by hyperphosphorylated tau protein. In recent years, neuroinflammation has been recognized as a key driver in the pathogenesis of AD, and microglia, as innate immune cells of the central nervous system, play a central role in regulating the onset and progression of neuroinflammation. Lysosomes are key organelles within microglia responsible for degrading pathological proteins and regulating inflammatory signaling; dysfunction of lysosomes in microglia severely impairs their ability to clear Aβ, damaged proteins, and cellular debris, thereby promoting inflammatory responses. This manuscript summarizes upstream mechanisms that may influence microglial lysosomal dysfunction from four perspectives: pathological proteins, genetic factors, lipid metabolism disorders, and proinflammatory cytokines. Pathological proteins can impair lysosomal acidification and biogenesis by interfering with key pathways such as the TFEB-v-ATPase axis; various genetic factors exacerbate functional dysregulation by influencing the expression of lysosome-related genes and lipid metabolism; lipid metabolism disorders promote lysosomal membrane permeabilization, block the autophagy cascade and activate the inflammasome; proinflammatory cytokines can exert varying effects on the clearance of pathological substrates and by regulating lysosomal function. The aforementioned factors can influence microglial lysosomal function through various mechanisms, thereby contributing to impaired clearance of pathological substrates and the onset and progression of neuroinflammation. Intervention strategies targeting microglial lysosomal dysfunction, including enhancing lysosomal degradation capacity, regulating autophagy related pathways, correcting cellular metabolic dysregulation and suppressing excessive neuroinflammation, may offer new avenues for AD treatment.
