Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain.
Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain.
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DOI：
10.1111/bpa.12216
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Medical Research Council Cognitive Function and Ageing Study
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文献类型：
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作者：
Al-Mashhadi S;Simpson JE;Heath PR;Dickman M;Forster G;Matthews FE;Brayne C;Ince PG;Wharton SB;Medical Research Council Cognitive Function and Ageing Study
白质损伤(WML)在脑老化中很常见，并与痴呆症有关。我们的目的是研究在有病变的病例中，WML和明显正常的白质中是否存在DNA氧化损伤。WML的组织和对照白质来自有病变的脑组织(对照皮损)和无病变的脑白质(对照非皮损)，使用死后磁共振成像引导采样，来自医学研究委员会的认知功能和老龄化研究。8-羟基-2‘-脱氧鸟苷(8-OHdG)免疫组织化学染色和免疫印迹法检测丙二醛对氧化损伤的影响。用磷酸化组蛋白H_2AX(γH_2AX)、P53、衰老标志物和定量逆转录聚合酶链式反应(RT-PCR板)检测DNA损伤相关候选基因。8-羟色胺在胶质细胞和血管内皮细胞中均有表达，白细胞性白血病和对照组皮损中8-羟色胺的表达均高于对照组非皮损组(P <； 0.001)。γ-H_2AX表现相似，但组间差异较小(P = 0.03)。衰老相关的β半乳糖苷酶和p16的表达提示了胶质细胞衰老机制的诱导。氧化DNA损伤和DNA损伤反应是WML发病机制的特征，并提示胶质细胞功能障碍的候选机制。在WML患者中，它们在明显正常的白质中的表达表明，白质功能障碍并不局限于病变。这种场效应损伤的作用、发病机制和认知损害是有待确定的领域。
White matter lesions (WML) are common in brain aging and are associated with dementia. We aimed to investigate whether oxidative DNA damage and occur in WML and in apparently normal white matter in cases with lesions. Tissue from WML and control white matter from brains with lesions (controls lesional) and without lesions (controls non‐lesional) were obtained, using post‐mortem magnetic resonance imaging‐guided sampling, from the Medical Research Council Cognitive Function and Ageing Study. Oxidative damage was assessed by immunohistochemistry to 8‐hydroxy‐2′‐deoxoguanosine (8‐OHdG) and Western blotting for malondialdehyde. DNA response was assessed by phosphorylated histone H2AX (γH2AX), p53, senescence markers and by quantitative Reverse transcription polymerase chain reaction (RT‐PCR) panel for candidate DNA damage‐associated genes. 8‐OHdG was expressed in glia and endothelium, with increased expression in both WML and controls lesional compared with controls non‐lesional (P < 0.001). γH2Ax showed a similar, although attenuated difference among groups (P = 0.03). Expression of senescence‐associated β‐galactosidase and p16 suggested induction of senescence mechanisms in glia. Oxidative DNA damage and a DNA damage response are features of WML pathogenesis and suggest candidate mechanisms for glial dysfunction. Their expression in apparently normal white matter in cases with WML suggests that white matter dysfunction is not restricted to lesions. The role of this field‐effect lesion pathogenesis and cognitive impairment are areas to be defined.