title: Amyloid-beta peptide enhances tumor necrosis factor-alpha-induced iNOS through neutral sphingomyelinase/ceramide pathway in oligodendrocytes.
abstract: 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 (Abeta) on proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha)-induced inducible nitric oxide synthase (iNOS) in cultured oligodendrocytes (OLGs). Although Abeta 25-35 by itself had little effect on iNOS mRNA, protein, and nitrite production, it enhanced TNF-alpha-induced iNOS expression and nitrite generation in OLGs. Abeta, 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 iNOS 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 Abeta. Overexpression of a truncated mutant of nSMase with a dominant negative function inhibited iNOS mRNA production. 3-OMS also inhibited nuclear factor kappaB (NF-kappaB) binding activity induced by TNF-alpha or by the combination of TNF-alpha and Abeta. These results suggest that neutral sphingomyelinase/ceramide pathway is required but may not be sufficient for iNOS expression induced by TNF-alpha and the combination of TNF-alpha and Abeta.
authors: Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: C
authors: C
authors: Zeng
authors: J T
authors: JT
authors: Lee
authors: H
authors: H
authors: Chen
authors: S
authors: S
authors: Chen
authors: C Y
authors: CY
authors: Hsu
authors: J
authors: J
authors: Xu
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology; D002855:Chromatography, Thin Layer / Q000379:methods; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007239:Infections; D016296:Mutagenesis / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000201:enzymology; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism* / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002518:Ceramides; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009573:Nitrites; D010446:Peptide Fragments; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013108:Sphingomyelin Phosphodiesterase; C022616:thiazolyl blue