Neutral Sphingomyelinase 2 Mediates Oxidative Stress Effects on Astrocyte Senescence and Synaptic Plasticity Transcripts

Zhihui Zhu, Zainuddin Quadri, Simone M. Crivelli, Ahmed Elsherbini, Liping Zhang, Priyanka Tripathi, Haiyan Qin, Emily Roush, Stefka D. Spassieva, Mariana Nikolova-Karakashian, Timothy S. McClintock, Erhard Bieberich

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


We have shown that deficiency of neutral sphingomyelinase 2 (nSMase2), an enzyme generating the sphingolipid ceramide, improves memory in adult mice. Here, we performed sphingolipid and RNA-seq analyses on the cortex from 10-month-old nSMase2-deficient (fro/fro) and heterozygous (+ /fro) mice. fro/fro cortex showed reduced levels of ceramide, particularly in astrocytes. Differentially abundant transcripts included several functionally related groups, with decreases in mitochondrial oxidative phosphorylation and astrocyte activation transcripts, while axon guidance and synaptic transmission and plasticity transcripts were increased, indicating a role of nSMase2 in oxidative stress, astrocyte activation, and cognition. Experimentally induced oxidative stress decreased the level of glutathione (GSH), an endogenous inhibitor of nSMase2, and increased immunolabeling for ceramide in primary + /fro astrocytes, but not in fro/fro astrocytes. β-galactosidase activity was lower in 5-week-old fro/fro astrocytes, indicating delayed senescence due to nSMase2 deficiency. In fro/fro cortex, levels of the senescence markers C3b and p27 and the proinflammatory cytokines interleukin 1β, interleukin 6, and tumor necrosis factor α were reduced, concurrent with twofold decreased phosphorylation of their downstream target, protein kinase Stat3. RNA and protein levels of the ionotropic glutamate receptor subunit 2B (Grin2b/NR2B) were increased by twofold, which was previously shown to enhance cognition. This was consistent with threefold reduced levels of exosomes carrying miR-223-3p, a micro-RNA downregulating NR2B. In summary, our data show that nSMase2 deficiency prevents oxidative stress-induced elevation of ceramide and secretion of exosomes by astrocytes that suppress neuronal function, indicating a role of nSMase2 in the regulation of neuroinflammation and cognition.

Original languageEnglish
Pages (from-to)3233-3253
Number of pages21
JournalMolecular Neurobiology
Issue number5
StatePublished - May 2022

Bibliographical note

Funding Information:
This work was supported in part by NIH grants R01NS095215, R01AG034389, and R01AG064234, and the VA grant I01BX003643 to EB. This work was also supported in part by a BrightFocus grant (A20201464F) to SMC. The lipidomics analysis of this study was supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313 and P30 GM103339).

Funding Information:
We thank the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky, Lexington, KY, for institutional support.

Publisher Copyright:
© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.


  • Ceramide
  • Extracellular vesicles
  • Grin2b
  • Oxidative stress

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience
  • Neuroscience (miscellaneous)


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