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

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

doi:10.1186/s40478-023-01633-7

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	135
Journal	Acta neuropathologica communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1186/s40478-023-01633-7
State	Published - Dec 2023

Bibliographical note

Funding Information:
Acknowledgement is made to the donors of ADR, a program of BrightFocus Foundation, for support of this research. Additionally, we would like to acknowledge the Markey Shared Resource Facility which is supported by the NCI Cancer Center Support Grant (P30 CA177558). In addition, we acknowledge the support of the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky College of Medicine.

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).

Funding Information:
Acknowledgement is made to the donors of ADR, a program of BrightFocus Foundation, for support of this research. Additionally, we would like to acknowledge the Markey Shared Resource Facility which is supported by the NCI Cancer Center Support Grant (P30 CA177558). In addition, we acknowledge the support of the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky College of Medicine.

Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.

Keywords

5xFAD
Acid sphingomyelinase
Astrocytes
C1q
Extracellular vesicle
IL-1α
Imipramine
Microglia
Mitochondria
TNF-α

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

Access to Document

10.1186/s40478-023-01633-7

Cite this

Crivelli, S. M., Quadri, Z., Vekaria, H. J., Zhu, Z., Tripathi, P., Elsherbini, A., Zhang, L., Sullivan, P. G., & Bieberich, E. (2023). Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse. Acta neuropathologica communications, 11(1), Article 135. https://doi.org/10.1186/s40478-023-01633-7

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abstract = "In Alzheimer{\textquoteright}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.",

keywords = "5xFAD, Acid sphingomyelinase, Astrocytes, C1q, Extracellular vesicle, IL-1α, Imipramine, Microglia, Mitochondria, TNF-α",

author = "Crivelli, {Simone M.} and Zainuddin Quadri and Vekaria, {Hemendra J.} and Zhihui Zhu and Priyanka Tripathi and Ahmed Elsherbini and Liping Zhang and Sullivan, {Patrick G.} and Erhard Bieberich",

note = "Funding Information: Acknowledgement is made to the donors of ADR, a program of BrightFocus Foundation, for support of this research. Additionally, we would like to acknowledge the Markey Shared Resource Facility which is supported by the NCI Cancer Center Support Grant (P30 CA177558). In addition, we acknowledge the support of the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky College of Medicine. 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). Funding Information: Acknowledgement is made to the donors of ADR, a program of BrightFocus Foundation, for support of this research. Additionally, we would like to acknowledge the Markey Shared Resource Facility which is supported by the NCI Cancer Center Support Grant (P30 CA177558). In addition, we acknowledge the support of the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky College of Medicine. Publisher Copyright: {\textcopyright} 2023, BioMed Central Ltd., part of Springer Nature.",

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month = dec,

doi = "10.1186/s40478-023-01633-7",

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Crivelli, SM, Quadri, Z, Vekaria, HJ, Zhu, Z, Tripathi, P, Elsherbini, A, Zhang, L, Sullivan, PG & Bieberich, E 2023, 'Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse', Acta neuropathologica communications, vol. 11, no. 1, 135. https://doi.org/10.1186/s40478-023-01633-7

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. et al.
In: Acta neuropathologica communications, Vol. 11, No. 1, 135, 12.2023.

Research output: Contribution to journal › Article › peer-review

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T1 - Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse

AU - Crivelli, Simone M.

AU - Quadri, Zainuddin

AU - Vekaria, Hemendra J.

AU - Zhu, Zhihui

AU - Tripathi, Priyanka

AU - Elsherbini, Ahmed

AU - Zhang, Liping

AU - Sullivan, Patrick G.

AU - Bieberich, Erhard

N1 - Funding Information: Acknowledgement is made to the donors of ADR, a program of BrightFocus Foundation, for support of this research. Additionally, we would like to acknowledge the Markey Shared Resource Facility which is supported by the NCI Cancer Center Support Grant (P30 CA177558). In addition, we acknowledge the support of the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky College of Medicine. 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). Funding Information: Acknowledgement is made to the donors of ADR, a program of BrightFocus Foundation, for support of this research. Additionally, we would like to acknowledge the Markey Shared Resource Facility which is supported by the NCI Cancer Center Support Grant (P30 CA177558). In addition, we acknowledge the support of the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky College of Medicine. Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - 5xFAD

KW - Acid sphingomyelinase

KW - Astrocytes

KW - C1q

KW - Extracellular vesicle

KW - IL-1α

KW - Imipramine

KW - Microglia

KW - Mitochondria

KW - TNF-α

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JO - Acta neuropathologica communications

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ER -

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

Abstract

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Keywords

ASJC Scopus subject areas

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