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

• Published in: Neurobiology of disease Vol. 17; no. 1; pp. 99 - 107
• Main Authors: Yang, Ding-I, Yeh, Chen-Hsiung, Chen, Shawei, Xu, Jan, Hsu, Chung Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2004; Elsevier
• Subjects: Acidic sphingomyelinase; Alzheimer's disease; Amyloid beta-Peptides - toxicity; Animals; Blood–brain barrier; Cell Death - drug effects; Cell Death - physiology; Cell Line; Ceramide; Cerebral amyloid angiopathy; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Enzyme Activation - drug effects; Enzyme Activation - physiology; Mice; Neuroglia - drug effects; Neuroglia - enzymology; Oxidative stress; Peptide Fragments - toxicity; Phosphodiesterase Inhibitors - pharmacology; Rats; Reactive oxygen species; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - metabolism; Sphingomyelinase; Oxidative stress; Cerebral amyloid angiopathy; Reactive oxygen species; Ceramide; Acidic sphingomyelinase; Sphingomyelinase; Alzheimer's disease; Blood–brain barrier
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2004.06.001

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.