Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse

Authors

Simone M. Crivelli, University of KentuckyFollow
Zainuddin Quadri, University of KentuckyFollow
Hemendra J. Vekaria, University of KentuckyFollow
Zhihui Zhu, University of KentuckyFollow
Priyanka Tripathi, University of KentuckyFollow
Ahmed Elsherbini, University of KentuckyFollow
Liping Zhang, University of KentuckyFollow
Patrick G. Sullivan, University of KentuckyFollow
Erhard Bieberich, University of KentuckyFollow

Abstract

In Alzheimer’s disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD mice treated with Imipramine contained reduced levels of the astrocytic marker GFAP, ceramide, and Aβ and did not impair mitochondrial respiration when compared to EVs derived from untreated 5xFAD brain. Consistently, Imipramine-treated 5xFAD mice showed reduced AD pathology. Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.

Document Type

Article

Publication Date

8-2023

Notes/Citation Information

© The Author(s) 2023. Open Access 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://creativeco mmons.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/s40478-023-01633-7

Funding Information

This work was supported by grants to EB (National Institutes of Health: R01AG064234, R21AG078601, RF1AG078338; U.S. Department of Veterans Affairs: I01BX003643) and to SMC (BrightFocus Grant Submission No.: A20201464F; National Institute On Aging of the National Institutes of Health under Award Number P30AG028383). PGS and HV received support from Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT chair #3).

Repository Citation

Crivelli, Simone M.; Quadri, Zainuddin; Vekaria, Hemendra J.; Zhu, Zhihui; Tripathi, Priyanka; Elsherbini, Ahmed; Zhang, Liping; Sullivan, Patrick G.; and Bieberich, Erhard, "Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse" (2023). Markey Cancer Center Faculty Publications. 349.
https://uknowledge.uky.edu/markey_facpub/349