Exercise alleviates cognitive dysfunction in Alzheimer’s disease mice via skeletal muscle-derived extracellular vesicles which enhance plaque clearance by microglia [RNA-Seq]

Exercise confers cognitive benefits in Alzheimer’s disease (AD), yet the underlying mechanisms remain incompletely understood. The 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 exercises promoted the secretion of skeletal muscle-derived extracellular vesicles (SKM-EVs), which subsequently pinocytosis by microglia. Gain- and loss-of-function experiments showed that exercised SKM-EVs activated the polarization of disease-associated microglia (DAM) and enhanced the clearance of amyloid-beta (Aβ) plaques. Furthermore, miR-378a-3p was identified as the key miRNA in SKM-EVs and promoted lipid metabolism in DAM by targeting p110α. Importantly, the therapeutic administration of EVs derived from mir-378a overexpressing myotubes alleviated cognitive impairment in AD mice. Together, our findings demonstrate that exercised SKM-EVs could serve as a novel myokine mediating communication from skeletal muscle to the brain and develop alternative therapeutic strategies for exercise in AD treatment.