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.

Document Type

Article

Publication Date

4-28-2020

Notes/Citation Information

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

© The Author(s). 2020

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Digital Object Identifier (DOI)

https://doi.org/10.1186/s40478-020-00931-8

Funding Information

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).

Related Content

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

Click here to access the above article from UKnowledge.

40478_2020_931_MOESM1_ESM.pdf (769 kB)
Additional file 1

Share

COinS