Association of A? with ceramide-enriched astrosomes mediates A? neurotoxicity.

ABSTRACT: 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.

SUBMITTER: Elsherbini A 

PROVIDER: S-EPMC7189561 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature