Association of A\u03b2 with ceramide-enriched astrosomes mediates A\u03b2 neurotoxicity

Ahmed Elsherbini,Michael B Dinkins,Zhihui Zhu,Priyanka Tripathi,Haiyan Qin,Simone M Crivelli,Alexander S Kirov,Erhard Bieberich,Guanghu Wang

doi:10.1186/s40478-020-00931-8

Abstract

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.

Highlights

Aβ plaque deposits and tau neurofibrillary tangle formation are hallmarks of Alzheimer’s disease (AD) [2, 62]
Using a method developed in our laboratory, lipid-mediated affinity chromatography (LIMAC) of vesicles with anti-ceramide antibody [3], we showed for the first time that astrosomes from serum were ceramide-enriched and associated with Aβ
We previously reported that the neutral sphingomyelinase 2 (nSMase2)- deficient 5XFAD mice showed a reduced number of brain exosomes, ceramide levels, glial activation, total Aβ42 and plaque burden, and improved recognition in a fear-conditioned learning task

Summary

Introduction

Aβ plaque deposits and tau neurofibrillary tangle formation are hallmarks of AD [2, 62]. It is still controversial which of the two factors is critical for neuronal dysfunction and death, leading to cognitive decline and demise of the patient. Most of the previous studies assumed that the buildup of Aβ or tau by themselves induces neurotoxicity [47, 55, 70] This assumption, was in stark contrast to observations in AD mouse models and patients showing significant buildup of plaques and tangles without obvious neuronal cell death [62]. Based on our previous studies showing that Aβ associates with astrocyte-derived exosomes

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Discussion

Conclusion