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

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)99-107
Number of pages9
JournalNeurobiology of Disease
Volume17
Issue number1
DOIs
Publication statusPublished - Oct 2004

Keywords

  • Acidic sphingomyelinase
  • Alzheimer's disease
  • Blood-brain barrier
  • Ceramide
  • Cerebral amyloid angiopathy
  • Oxidative stress
  • Reactive oxygen species
  • Sphingomyelinase

ASJC Scopus subject areas

  • Neurology

Fingerprint Dive into the research topics of 'Neutral sphingomyelinase activation in endothelial and glial cell death induced by amyloid beta-peptide'. Together they form a unique fingerprint.

Cite this