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.

中文翻译：

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Aβ与富含神经酰胺的星形小体的关联介导了Aβ神经毒性。

淀粉样蛋白-β（Aβ）与称为外泌体的细胞外囊泡相关。目前尚不清楚外泌体是否以及如何调节阿尔茨海默氏病（AD）中的Aβ神经毒性。我们在这里显示，来自家族性AD（5xFAD）转基因小鼠模型的脑组织和血清以及来自AD患者的血清包含与Aβ相关的富含神经酰胺和星形胶质细胞的外泌体（称为星状体）。在Neuro-2a细胞，原代培养的神经元和人诱导的多能干细胞衍生的神经元中，将来自5xFAD小鼠和AD患者血清的Aβ相关星状体特异性转运至线粒体，诱导线粒体聚集，并上调裂变蛋白Drp-1在对应于5飞克Aβ/ L培养基的浓度。Aβ相关星体，但不是野生型或对照人血清外泌体，介导的Aβ结合到电压依赖性阴离子通道1（VDAC1），并随后激活胱天蛋白酶。Aβ相关的星形小体诱导神经突碎裂和神经元细胞死亡，这表明与星形小体的缔合实质上增强了AD中Aβ的神经毒性，并且可能构成治疗的新靶点。