Neutral sphingomyelinase activation in endothelial and glial cell death induced by amyloid beta-peptide

Ding I. Yang, Chen Hsiung Yeh, Shawei Chen, Jan Xu, Chung Y. Hsu

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35 引文 斯高帕斯(Scopus)


We have explored the molecular mechanism underlying amyloid beta-peptide (Aβ)-mediated cytotoxicity in vitro. Exposure of murine cerebral endothelial cells (CECs) or C6 glioma cells to Aβ25-35 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 Aβ25-35 cytotoxicity in both CECs and C6 glioma cells. Aβ25-35-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 Aβ25-35 in CECs. Furthermore, genetic knockdown of nSMase by an antisense strategy rendered C6 glioma cells specifically resistant to Aβ25-35 cytotoxicity without affecting their vulnerability to serum deprivation. Together, nSMase activation with subsequent ceramide production may contribute, at least partially, to Aβ25-35 cytotoxicity in cell types with cerebral endothelial and glial lineage.
頁(從 - 到)99-107
期刊Neurobiology of Disease
出版狀態已發佈 - 十月 2004

ASJC Scopus subject areas

  • 神經內科


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