Related Experiment Video
Updated: Sep 30, 2025
06:43
A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
12.3K
Neutral Sphingomyelinase 2 Mediates Oxidative Stress Effects on Astrocyte Senescence and Synaptic Plasticity
Zhihui Zhu1, Zainuddin Quadri1,2, Simone M Crivelli1
1Department of Physiology, College of Medicine, University of Kentucky, 780 Rose St., Room MS519, Lexington, KY, 40536, USA.
Molecular Neurobiology
|March 16, 2022
Summary
Neutral sphingomyelinase 2 (nSMase2) deficiency improves memory by reducing ceramide, oxidative stress, and neuroinflammation in mice. This enhances synaptic plasticity and cognitive function.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Neutral sphingomyelinase 2 (nSMase2) generates ceramide, a sphingolipid implicated in various cellular processes.
- nSMase2 activity and ceramide levels are linked to cognitive function and neuroinflammation.
- Previous studies suggest nSMase2 deficiency may impact memory.
Purpose of the Study:
- To investigate the molecular mechanisms by which nSMase2 deficiency impacts brain function, particularly in relation to ceramide metabolism, oxidative stress, and cognition.
- To analyze sphingolipid and transcriptomic changes in the cortex of nSMase2-deficient mice.
- To explore the role of nSMase2 in astrocyte activation, senescence, and neuroinflammation.
Main Methods:
- Sphingolipid analysis and RNA sequencing (RNA-seq) on mouse cortical tissue.
- Experimental induction of oxidative stress in primary astrocytes.
- Measurement of β-galactosidase activity to assess senescence.
- Analysis of senescence markers, proinflammatory cytokines, and signaling pathways (e.g., Stat3 phosphorylation).
- Quantification of ionotropic glutamate receptor subunit 2B (NR2B) and exosomal microRNA levels.
Main Results:
- nSMase2 deficiency (fro/fro) reduced cortical ceramide levels, particularly in astrocytes.
- Decreased transcripts related to mitochondrial oxidative phosphorylation and astrocyte activation were observed.
- Increased transcripts associated with axon guidance, synaptic transmission, and plasticity were found in fro/fro mice.
- Experimentally induced oxidative stress increased ceramide in wild-type astrocytes but not in nSMase2-deficient astrocytes.
- nSMase2 deficiency delayed astrocyte senescence and reduced levels of senescence markers and proinflammatory cytokines.
- NR2B levels were increased, while exosomes carrying miR-223-3p were reduced in fro/fro mice.
Conclusions:
- nSMase2 deficiency mitigates oxidative stress-induced ceramide elevation and astrocyte-derived exosome secretion.
- nSMase2 plays a critical role in regulating neuroinflammation and cognitive function.
- Targeting nSMase2 may offer a therapeutic strategy for cognitive disorders associated with oxidative stress and neuroinflammation.
