期刊
JOURNAL OF NEUROCHEMISTRY
卷 94, 期 3, 页码 703-712出版社
WILEY
DOI: 10.1111/j.1471-4159.2005.03217.x
关键词
amyloid beta-peptide 25-35; ceramide; inducible nitric oxide synthase; neutral sphingomyelinase; oligodendrocyte; tumor necrosis factor-alpha
资金
- NINDS NIH HHS [NS40162, R01 NS40525] Funding Source: Medline
- BHP HRSA HHS [AHA 0050597N] Funding Source: Medline
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.
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