Amyloid-beta peptide enhances tumor necrosis factor-alpha-induced iNOS through neutral sphingomyelinase/ceramide pathway in oligodendrocytes.
Amyloid-beta peptide enhances tumor necrosis factor-alpha-induced iNOS through neutral sphingomyelinase/ceramide pathway in oligodendrocytes.
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淀粉样蛋白-β 肽通过少突胶质细胞中的中性鞘磷脂酶/神经酰胺途径增强肿瘤坏死因子-α 诱导的 iNOS。
DOI：
10.1111/j.1471-4159.2005.03217.x
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发表时间：
2005
影响因子：
4.7
通讯作者：
Xu,J
中科院分区：
文献类型：
--
作者：
Zeng,C;Lee,JT;Chen,H;Chen,S;Hsu,CY;Xu,J
虽然越来越多的证据表明，白色物质退化有助于阿尔茨海默病（AD）的病理，其潜在的机制是未知的。为了研究淀粉样β肽在诱导AD患者白色物质氧化应激损伤中的作用，我们研究了淀粉样β肽25-35（Aβ）对促炎细胞因子肿瘤坏死因子-α（TNF-α）诱导的少突胶质细胞（OLG）诱导型一氧化氮合酶（iNOS）的影响。虽然Aβ 25-35本身对iNOS mRNA、蛋白和亚硝酸盐产生的影响很小，但它增强了OLG中TNF-α诱导的iNOS表达和亚硝酸盐产生。Aβ、TNF-α或两者的组合可增加中性鞘磷脂酶（nSMase）活性，但不增加酸性鞘磷脂酶（aSMase）活性，导致神经酰胺蓄积。细胞渗透性C2-神经酰胺增强TNF-α诱导的iNOS表达和亚硝酸盐生成。此外，特异性nSMase抑制剂3-O-甲基鞘磷脂（3-OMS）可抑制TNF-α或TNF-α和Aβ联合诱导的iNOS表达和亚硝酸盐生成。过表达的截短突变体的nSMase与显性负功能抑制iNOS mRNA的产生。3-OMS还抑制TNF-α或TNF-α和Aβ联合诱导的核因子κB（NF-κB）结合活性。这些结果表明，中性鞘磷脂酶/神经酰胺途径是必需的，但可能不足以诱导由TNF-α和TNF-α和Aβ的组合诱导的iNOS表达。
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‐β peptide in inducing oxidative stress damage in white matter of AD, we investigated the effects of amyloid‐β peptide 25–35 (Aβ) on proinflammatory cytokine tumor necrosis factor‐α (TNF‐α)‐induced inducible nitric oxide synthase (iNOS) in cultured oligodendrocytes (OLGs). Although Aβ 25–35 by itself had little effect on iNOS mRNA, protein, and nitrite production, it enhanced TNF‐α‐induced iNOS expression and nitrite generation in OLGs. Aβ, TNF‐α, 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‐α‐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‐α or by the combination of TNF‐α and Aβ. Overexpression of a truncated mutant of nSMase with a dominant negative function inhibited iNOS mRNA production. 3‐OMS also inhibited nuclear factor κB (NF‐κB) binding activity induced by TNF‐α or by the combination of TNF‐α and Aβ. These results suggest that neutral sphingomyelinase/ceramide pathway is required but may not be sufficient for iNOS expression induced by TNF‐α and the combination of TNF‐α and Aβ.