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

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

  • Nat Aging. 2026 Mar;6(3):579-596. doi: 10.1038/s43587-026-01075-5.
Jiaquan Lin # 1 2 3 4,  Xiaoyan Shao # 1 2 3 4 5,  Tianshu Shi # 1 2 3,  Haosheng Wang 1 2 3 4,  Pan Zhang 1 2 3 4,  Yining Zhou 1 2 3 4,  Na Liu 1 2 3 4,  Yi He 1 2 3 4,  Depeng Fang 1 2 3 4,  Yong Shi 1 2 3,  Yuze Ma 1 2 3,  Bin Liu 1 2 3,  Wang Gong 1 2 3,  Wenshu Wu 1 2 3,  Rui Peng 1 2 3,  Chengzhi Wang 1 2 3 4,  Tao Shen 1 2 3,  Zhuoying Jiang 1 2 3 4,  Yu Ben 1 2 3,  Jianghui Qin 1 2 3,  Zhihong Xu 1 2 3,  Xiang Chen 6 7 8 9,  Qing Jiang 10 11 12,  Baosheng Guo 13 14 15 16 17
Affiliations

Affiliations

  • 1 Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China.
  • 3 National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, PR China.
  • 4 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, PR China.
  • 5 Department of Rheumatology and Immunology, Children's Hospital of Nanjing Medical University, Nanjing, PR China.
  • 6 Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China. [email protected].
  • 7 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China. [email protected].
  • 8 National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, PR China. [email protected].
  • 9 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, PR China. [email protected].
  • 10 Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China. [email protected].
  • 11 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China. [email protected].
  • 12 National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, PR China. [email protected].
  • 13 Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China. [email protected].
  • 14 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China. [email protected].
  • 15 National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, PR China. [email protected].
  • 16 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, PR China. [email protected].
  • 17 Department of Orthopaedics, Nanjing Central Hospital, Nanjing, PR China. [email protected].
  • # Contributed equally.
PMID: 41772068 DOI: 10.1038/s43587-026-01075-5
Abstract

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.

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