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Neutral sphingomyelinase activation in endothelial and glial cell death induced by amyloid beta-peptide
Ding-I Yang1, Chen-Hsiung Yeh, Shawei Chen
1Institute of Neuroscience, Tzu Chi University, Hualien 970, Taiwan, ROC.
Abstract:
We have explored the molecular mechanism underlying amyloid beta-peptide (Abeta)-mediated cytotoxicity in vitro. Exposure of murine cerebral endothelial cells (CECs) or C6 glioma cells to Abeta25-35 resulted in dose-dependent cell death. Ceramide is a pro-apoptotic lipid mediator. Forced elevation of cellular ceramide levels, either by application of an exogenous C2 ceramide analogue or bacterial sphingomyelinase that induces endogenous ceramide release from sphingomyelin, mimicked Abeta25-35 cytotoxicity in both CECs and C6 glioma cells. Abeta25-35-induced synthesis of ceramide was selectively mediated by activation of neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase (aSMase) or ceramide synthase. Both 3-O-Me-SM and N-acetyl-L-cysteine, the selective and nonselective pharmacological inhibitors of nSMase, respectively, suppressed nSMase activation, ceramide production, and cytotoxic action induced by Abeta25-35 in CECs. Furthermore, genetic knockdown of nSMase by an antisense strategy rendered C6 glioma cells specifically resistant to Abeta25-35 cytotoxicity without affecting their vulnerability to serum deprivation. Together, nSMase activation with subsequent ceramide production may contribute, at least partially, to Abeta25-35 cytotoxicity in cell types with cerebral endothelial and glial lineage.
Insights
Amyloid beta-peptide (Abeta) causes cell death by increasing ceramide, a pro-apoptotic lipid. Neutral sphingomyelinase (nSMase) activation is key to this Abeta-induced ceramide production and cytotoxicity.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Amyloid beta-peptide (Abeta) is implicated in neurodegenerative diseases.
- Abeta-mediated cytotoxicity is not fully understood at the molecular level.
- Ceramide is a known pro-apoptotic lipid mediator.
Purpose of the Study:
- To elucidate the molecular mechanism of Abeta-induced cytotoxicity.
- To investigate the role of ceramide in Abeta toxicity.
- To identify the specific enzymes involved in ceramide production.
Main Methods:
- Exposure of murine cerebral endothelial cells (CECs) and C6 glioma cells to Abeta25-35.
- Forced elevation of cellular ceramide levels using exogenous analogues or bacterial sphingomyelinase.
- Pharmacological inhibition and genetic knockdown of neutral sphingomyelinase (nSMase).
Main Results:
- Abeta25-35 induced dose-dependent cell death in CECs and C6 glioma cells.
- Elevated ceramide levels mimicked Abeta25-35 cytotoxicity.
- Abeta-induced ceramide synthesis was mediated by nSMase activation, not acidic sphingomyelinase or ceramide synthase.
- Inhibitors of nSMase and genetic knockdown of nSMase suppressed Abeta-induced cytotoxicity.
Conclusions:
- nSMase activation and subsequent ceramide production contribute to Abeta-induced cytotoxicity.
- This mechanism is relevant in cell types of cerebral endothelial and glial lineage.
- Targeting nSMase may offer a therapeutic strategy for Abeta-related pathologies.
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