Amyloid-β peptide enhances tumor necrosis factor-α-induced NOS through neutral sphingomyelinase/ceramide pathway in oligodendrocytes

被引:59
作者
Zeng, C [1 ]
Lee, JT [1 ]
Chen, H [1 ]
Chen, S [1 ]
Hsu, CY [1 ]
Xu, J [1 ]
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
关键词
amyloid beta-peptide 25-35; ceramide; inducible nitric oxide synthase; neutral sphingomyelinase; oligodendrocyte; tumor necrosis factor-alpha;
D O I
10.1111/j.1471-4159.2005.03217.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Although accumulating evidence demonstrates that white matter degeneration contributes to pathology in Alzheimer's disease (AD), the underlying mechanisms are unknown. In order to study the roles of the amyloid-beta peptide in inducing oxidative stress damage in white matter of AD, we investigated the effects of amyloid-beta peptide 25-35 (A beta) on proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha)-induced inducible nitric oxide synthase (NOS) in cultured oligodendrocytes (OLGs). Although A beta 25-35 by itself had little effect on NOS mRNA, protein, and nitrite production, it enhanced TNF-alpha-induced NOS expression and nitrite generation in OLGs. A beta, TNF-alpha, or the combination of both, increased neutral sphingomyelinase (nSMase) activity, but not acidic sphingomyelinase (aSMase) activity, leading to ceramide accumulation. Cell permeable C2-ceramide enhanced TNF-alpha-induced NOS expression and nitrite generation. Moreover, the specific nSMase inhibitor, 3-O-methyl-sphingomyelin (3-OMS), inhibited iNOS expression and nitrite production induced by TNF-alpha. or by the combination of TNF-alpha and A. Overexpression of a truncated mutant of nSMase with a dominant negative function inhibited NOS mRNA production. 3-OMS also inhibited nuclear factor kappa B (NF-kappa B) binding activity induced by TNF-alpha or by the combination of TNF-a and A beta. These results suggest that neutral sphingomyelinase/ceramide pathway is required but may not be sufficient for NOS expression induced by TNF-alpha and the combination of TNF-alpha and A beta.
引用
收藏
页码:703 / 712
页数:10
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