Neutral sphingomyelinase activation in endothelial and glial cell death induced by amyloid beta-peptide.
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.
Yang
Ding-I
DI
Institute of Neuroscience, Tzu Chi University, Hualien 970, Taiwan, ROC.
Yeh
Chen-Hsiung
CH
Chen
Shawei
S
Xu
Jan
J
Hsu
Chung Y
CY
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology; D010446:Peptide Fragments / Q000633:toxicity*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; C074636:amyloid beta-protein (25-35); D013108:Sphingomyelin Phosphodiesterase