Amyloid-β (Aβ) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate Aβ neurotoxicity in Alzheimer's disease (AD). We show here that brain tissue and serum from the transgenic mouse model of familial AD (5xFAD) and serum from AD patients contains ceramide-enriched and astrocyte-derived exosomes (termed astrosomes) that are associated with Aβ. In Neuro-2a cells, primary cultured neurons, and human induced pluripotent stem cell-derived neurons, Aβ-associated astrosomes from 5xFAD mice and AD patient serum were specifically transported to mitochondria, induced mitochondrial clustering, and upregulated the fission protein Drp-1 at a concentration corresponding to 5 femtomoles Aβ/L of medium. Aβ-associated astrosomes, but not wild type or control human serum exosomes, mediated binding of Aβ to voltage-dependent anion channel 1 (VDAC1) and subsequently, activated caspases. Aβ-associated astrosomes induced neurite fragmentation and neuronal cell death, suggesting that association with astrosomes substantially enhances Aβ neurotoxicity in AD and may comprise a novel target for therapy.

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Published in Acta Neuropathologica Communications, v. 8, issue 1, article no. 60.

© The Author(s). 2020

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This study was (in part) supported by grants from the National Institutes of Health (R01AG034389, R01NS095215, and R01AG064234) and the Department of Veteran Affairs (I01BX003643).

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All data generated or analysed during this study are included in this published article [and its supplementary information files].

Elsherbini, A., Qin, H., Zhu, Z., Tripathi, P., Crivelli, S.M., & Bieberich, E. (2020). In vivo evidence of exosome-mediated Aβ neurotoxicity. Acta Neuropathologica Communications, 8(1). https://doi.org/10.1186/s40478-020-00981-y

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