TY - JOUR
T1 - Neutral sphingomyelinase activation in endothelial and glial cell death induced by amyloid beta-peptide
AU - Yang, Ding I.
AU - Yeh, Chen Hsiung
AU - Chen, Shawei
AU - Xu, Jan
AU - Hsu, Chung Y.
N1 - Funding Information:
This work was supported by an NIH grant (NS41525) and a National Science Council in Taiwan grant (NSC92-2321-B-038-003) to Chung Y. Hsu and National Science Council in Taiwan (NSC92-2314-B-320-003) to Ding-I Yang.
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
KW - Acidic sphingomyelinase
KW - Alzheimer's disease
KW - Blood-brain barrier
KW - Ceramide
KW - Cerebral amyloid angiopathy
KW - Oxidative stress
KW - Reactive oxygen species
KW - Sphingomyelinase
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U2 - 10.1016/j.nbd.2004.06.001
DO - 10.1016/j.nbd.2004.06.001
M3 - Article
C2 - 15350970
AN - SCOPUS:4444370898
SN - 0969-9961
VL - 17
SP - 99
EP - 107
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -