Association of A with ceramide-enriched astrosomes mediates A neurotoxicity

Amyloid- (A) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate A 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 A. In Neuro-2a cells, primary cultured neurons, and human induced pluripotent stem cell-derived neurons, A-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 A/L of medium. A-associated astrosomes, but not wild type or control human serum exosomes, mediated binding of A to voltage-dependent anion channel 1 (VDAC1) and subsequently, activated caspases. A-associated astrosomes induced neurite fragmentation and neuronal cell death, suggesting that association with astrosomes substantially enhances A neurotoxicity in AD and may comprise a novel target for therapy.