Rapamycin ameliorates cognitive impairment by activating microglial amyloid-β degradation in mouse models of amyloidosis

Alzheimer's disease (AD) lacks effective treatments despite being the most prevalent dementia. This study examines whether rapamycin, an mTOR inhibitor with immunomodulatory properties, alleviates AD pathology by regulating microglia (the brain's resident immune cells).Rapamycin was administered orally to 2-month-old 5×FAD and hAPPNL-G-F mice, two amyloid plaque-dominant AD models. Behavioral and AD-pathological assessments were performed at approximately 5 months of age. Primary microglia exposed to rapamycin and fluorescently labeled amyloid-β (Aβ) oligomers were analyzed for phagocytic and degradative functions. The BV2 microglial cell line received rapamycin, oleic acid, and autophagy inhibitors to investigate mechanisms underlying rapamycin-regulated microglial degradation capacity. Oral rapamycin administration significantly reduced cerebral Aβ plaque burden, diminished dystrophic neurites, suppressed glial hyperactivation, and increased plaque-proximal microglial density in both 5×FAD and hAPPNL-G-F mice, ultimately mitigating memory deficits. Mechanistic investigations revealed rapamycin-activated microglial lysosomal degradation pathways, stimulated lipid droplet clearance in BV2 microglia, and enhanced Aβ phagocytic clearance in primary microglia. Our findings provide compelling evidence that rapamycin enhances Aβ clearance by targeting microglial lysosomal function, thereby establishing a novel glia-directed therapeutic strategy for AD.