Aspirin Induces Lysosomal Biogenesis and Attenuates Amyloid Plaque Pathology in a Mouse Model of Alzheimer's Disease via PPARα

Lysosomes play a central role in cellular homeostasis by regulating the cellular degradative machinery. Because aberrant lysosomal function has been associated with multiple lysosomal storage and neurodegenerative disorders, enhancement of lysosomal clearance has emerged as an attractive therapeutic strategy. Transcription factorEB(TFEB) is known as a master regulator of lysosomal biogenesis and, here, we reveal that aspirin, one of the most widely used medications in the world, upregulates TFEB and increases lysosomal biogenesis in brain cells. Interestingly, aspirin induced the activation of peroxisome proliferator-activated receptor alpha (PPAR alpha) and stimulated the transcription of Tfeb via PPAR alpha. Finally, oral administration of low-dose aspirin decreased amyloid plaque pathology in both male and female 5X familial Alzheimer's disease (5XFAD) mice in a PPAR alpha-dependent fashion. This study reveals a new function of aspirin in stimulating lysosomal biogenesis via PPAR alpha and suggests that low-dose aspirinmaybe used in lowering storage materials in Alzheimer's disease and lysosomal storage disorders.