Mitochondria-derived extracellular vesicles mediate Alzheimer’s disease pathology through transmitting microglial Ggt1

Extracellular vesicles (EVs) can modify pathological progression in Alzheimer’s disease (AD), the most common neurodegenerative disease in older adults, by spreading pathogenic factors. However, the function of mitovesicles (mtVs)—a recently identified subset of EVs—in AD remain unknown. Here we show that release of mtVs is enriched in brain tissue from patients with AD and 5×FAD mice. Administration of 5×FAD mouse brain-derived mtVs (ADmtVs) induced AD-like behavioral and pathological changes in wild-type mice and accelerated disease progression of AD mice. Moreover, the release of mtVs was regulated by mitochondrial respiratory metabolism, and blocking the release of mtVs significantly alleviated AD-like phenotypes. Proteomic analysis identified Ggt1 as a highly enriched protein in ADmtVs. Inhibiting Ggt1 expression and activity mitigated AD-like phenotypes of 5×FAD mice and delayed ADmtV-induced disease progression, suggesting Ggt1 as a pathological cargo of ADmtVs. Our findings highlight the pathological roles of mtVs in AD and highlight mtVs and Ggt1 as potential therapeutic targets. Li, Xia, Sun, Jia et al. identify a pathological role for mitovesicles in Alzheimer’s disease using patient brain samples and mouse models. Within mitovesicles, the authors identify Ggt1 as an enriched component, implicated in driving pathology.