Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice

  • Nat Neurosci. 2026 Jul;29(7):1573-1584. doi: 10.1038/s41593-026-02317-w.
Chensi Liang  1 ,  Yulan Zhou  1 ,  Kai Zhuang  1 ,  Shuzhong Wang  1 ,  Li Zhong  1 ,  Dan Can  1 ,  Aiyu Lei  1 ,  Huifang Li  1 ,  Jie Zhang  2  3  4 ,  Lige Leng  5  6  7
Affiliations
  • 1. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
  • 2. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • 3. Zhongshan Hospital, Xiamen University, Xiamen, China. [email protected].
  • 4. The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China. [email protected].
  • 5. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • 6. The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China. [email protected].
  • 7. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen, China. [email protected].
PMID: 42192197 DOI: 10.1038/s41593-026-02317-w
Abstract

Alzheimer's Disease (AD) is an irreversible Neurodegenerative Disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic Melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.

Products