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

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 microg...

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Autores principales: Crivelli, Simone M., Quadri, Zainuddin, Vekaria, Hemendra J., Zhu, Zhihui, Tripathi, Priyanka, Elsherbini, Ahmed, Zhang, Liping, Sullivan, Patrick G., Bieberich, Erhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440899/
https://www.ncbi.nlm.nih.gov/pubmed/37605262
http://dx.doi.org/10.1186/s40478-023-01633-7
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author Crivelli, Simone M.
Quadri, Zainuddin
Vekaria, Hemendra J.
Zhu, Zhihui
Tripathi, Priyanka
Elsherbini, Ahmed
Zhang, Liping
Sullivan, Patrick G.
Bieberich, Erhard
author_facet Crivelli, Simone M.
Quadri, Zainuddin
Vekaria, Hemendra J.
Zhu, Zhihui
Tripathi, Priyanka
Elsherbini, Ahmed
Zhang, Liping
Sullivan, Patrick G.
Bieberich, Erhard
author_sort Crivelli, Simone M.
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01633-7.
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spelling pubmed-104408992023-08-22 Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse Crivelli, Simone M. Quadri, Zainuddin Vekaria, Hemendra J. Zhu, Zhihui Tripathi, Priyanka Elsherbini, Ahmed Zhang, Liping Sullivan, Patrick G. Bieberich, Erhard Acta Neuropathol Commun Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01633-7. BioMed Central 2023-08-21 /pmc/articles/PMC10440899/ /pubmed/37605262 http://dx.doi.org/10.1186/s40478-023-01633-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://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.
spellingShingle Research
Crivelli, Simone M.
Quadri, Zainuddin
Vekaria, Hemendra J.
Zhu, Zhihui
Tripathi, Priyanka
Elsherbini, Ahmed
Zhang, Liping
Sullivan, Patrick G.
Bieberich, Erhard
Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse
title Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse
title_full Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse
title_fullStr Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse
title_full_unstemmed Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse
title_short Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse
title_sort inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves alzheimer’s disease pathology in the 5xfad mouse
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440899/
https://www.ncbi.nlm.nih.gov/pubmed/37605262
http://dx.doi.org/10.1186/s40478-023-01633-7
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