Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer's Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

译文

:醛脱氢酶2缺乏症(ALDH2 * 2)约5.6亿东亚人因饮酒而面部潮红。最近的荟萃分析表明,ALDH2 * 2突变与阿尔茨海默氏病(AD)之间存在潜在的联系。其他研究将长期饮酒与AD的危险因素联系起来。在本研究中,我们显示,AD患者的成纤维细胞在具有ApoEε4等位基因的AD患者的成纤维细胞中也具有ALDH2 * 2突变或ALDH2 * 2的过表达,表现出乙醛负荷增加,氧化应激和线粒体功能障碍相对性增加对健康受试者的治疗和暴露于乙醇会加剧这些功能障碍。在体内模型中,野生型小鼠每天暴露于乙醇达11周后会导致线粒体功能障碍,大脑中的氧化应激和醛水平升高,并且这些疾病在ALDH2 * 2 / * 2(纯合子)小鼠中更大。慢性乙醇暴露后,相对于野生型,ALDH2 * 2 / * 2小鼠的大脑中AD相关蛋白,淀粉样β-淀粉样蛋白和神经炎症的水平更高。相对于野生型WT小鼠的神经元或星形胶质细胞的反应,培养的ALDH2 * 2 / * 2小鼠的初级皮层神经元对乙醇的敏感性增加,并且其初级星形胶质细胞的活化更大。重要的是,ALDH2和ALDH2 * 2的激活剂Alda-1抑制了乙醇诱导的Aβ升高以及体内外的神经炎症。这些数据表明醛,特别是乙醇衍生的乙醛的代谢障碍是AD相关病理的一个原因,并突显了普通人群,尤其是携带ALDH2 * 2突变的东亚人的饮酒风险。

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