Exercise alleviates cognitive dysfunction in Alzheimer's disease mice via skeletal muscle-derived extracellular vesicles that enhance plaque clearance by microglia.

Exercise confers cognitive benefits in Alzheimer's disease (AD), yet the underlying mechanisms remain incompletely understood. Skeletal muscle functions as an endocrine organ that secretes myokines which affect the homeostasis of extra-muscular organs, including the brain. Here we found that swimming exercise promotes secretion of skeletal muscle-derived extracellular vesicles (SKM-EVs), which are subsequently taken up via pinocytosis by microglia. Gain-of-function and loss-of-function experiments showed that exercise-induced SKM-EVs induce polarization of disease-associated microglia and enhance the clearance of amyloid-beta plaques. Furthermore, miR-378a-3p was identified as a key microRNA cargo in SKM-EVs, regulating lipid metabolism in disease-associated microglia by targeting p110α. Importantly, administration of extracellular vesicles derived from miR-378a-overexpressing myotubes alleviated cognitive impairment in AD mice. Together, our findings demonstrate that exercise-induced SKM-EVs could serve as a myokine, mediating communication from skeletal muscle to the brain, providing a potential exercise-mimicking therapeutic strategy for AD.