1. Academic Validation
  2. Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer's disease pathology in the 5xFAD mouse

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

  • Acta Neuropathol Commun. 2023 Aug 21;11(1):135. doi: 10.1186/s40478-023-01633-7.
Simone M Crivelli 1 Zainuddin Quadri 1 Hemendra J Vekaria 2 3 4 Zhihui Zhu 1 Priyanka Tripathi 1 Ahmed Elsherbini 1 Liping Zhang 1 Patrick G Sullivan 2 3 4 Erhard Bieberich 5 6
Affiliations

Affiliations

  • 1 Department of Physiology, University of Kentucky College of Medicine, 780 Rose Street MS519, Lexington, KY, 40536, USA.
  • 2 Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA.
  • 3 Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY, USA.
  • 4 Veterans Affairs Medical Center, Lexington, KY, 40502, USA.
  • 5 Department of Physiology, University of Kentucky College of Medicine, 780 Rose Street MS519, Lexington, KY, 40536, USA. erhard.bieberich@uky.edu.
  • 6 Veterans Affairs Medical Center, Lexington, KY, 40502, USA. erhard.bieberich@uky.edu.
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.

Keywords

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

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