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

Swimming exercise promotes secretion of skeletal muscle-derived extracellular vesicles (SKM-EVs) that are taken up by microglia via pinocytosis.

• SKM-EVs were identified as a form of myokine mediating skeletal muscle-to-brain communication.
• Microglia internalize SKM-EVs through pinocytosis, a non-specific fluid-phase endocytic mechanism.
• Skeletal muscle functions as an endocrine organ that secretes factors affecting extra-muscular organ homeostasis including the brain.

Exercise-induced SKM-EVs induce polarization of disease-associated microglia and enhance clearance of amyloid-beta plaques.

• Both gain-of-function and loss-of-function experiments were conducted to establish the role of SKM-EVs in microglial polarization.
• SKM-EVs specifically promoted polarization of disease-associated microglia (DAM), a microglial subtype implicated in AD pathology.
• Enhanced microglial phagocytic activity led to increased amyloid-beta plaque clearance in AD mouse models.

miR-378a-3p was identified as the key microRNA cargo in SKM-EVs that regulates lipid metabolism in disease-associated microglia.

• miR-378a-3p was enriched in exercise-induced SKM-EVs and identified as the functionally critical cargo.
• The molecular target of miR-378a-3p was identified as p110α, a subunit involved in lipid metabolism signaling.
• miR-378a-3p regulates lipid metabolism in disease-associated microglia by targeting p110α.

Administration of extracellular vesicles derived from miR-378a-overexpressing myotubes alleviated cognitive impairment in AD mice.

• EVs were derived from myotubes engineered to overexpress miR-378a.
• Administration of these miR-378a-overexpressing myotube-derived EVs was sufficient to ameliorate cognitive dysfunction in AD mouse models.
• This finding supports the therapeutic potential of an exercise-mimicking strategy for Alzheimer's disease treatment.

Exercise-induced SKM-EVs represent a potential exercise-mimicking therapeutic strategy for Alzheimer's disease.

• The findings demonstrate that SKM-EVs mediate communication from skeletal muscle to the brain in the context of exercise.
• The SKM-EV/miR-378a-3p/p110α axis provides a mechanistic basis for the cognitive benefits of exercise in AD.
• The authors propose that administration of SKM-EVs or miR-378a-enriched EVs could serve as a pharmacological substitute for exercise benefits in AD patients.