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.

中文翻译：

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醛脱氢酶 2 活性和醛负荷有助于神经炎症和阿尔茨海默病相关病理学。

醛脱氢酶 2 缺乏症 (ALDH2*2) 导致约 5.6 亿东亚人因饮酒而面部潮红。最近的荟萃分析证明了 ALDH2*2 突变与阿尔茨海默病 (AD) 之间的潜在联系。其他研究已将长期饮酒与 AD 的危险因素联系起来。在本研究中，我们表明，来自携带 ApoE ε4 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 过表达的 AD 患者的成纤维细胞表现出醛负荷增加、氧化应激和线粒体功能障碍相对增加。健康受试者和接触乙醇加剧了这些功能障碍。在体内模型中，WT 小鼠每天暴露于乙醇 11 周导致线粒体功能障碍，ALDH2*2/*2（纯合子）小鼠大脑中的氧化应激和增加的醛水平以及这些病理情况更为严重。在慢性乙醇暴露后，与 WT 相比，ALDH2*2/*2 小鼠大脑中 AD 相关蛋白、淀粉样蛋白-β 和神经炎症的水平更高。ALDH2*2/*2 小鼠的培养的初级皮层神经元对乙醇的敏感性增加，并且相对于来自 WT 小鼠的神经元或星形胶质细胞的反应，它们的初级星形胶质细胞活化程度更高。重要的是，ALDH2 和 ALDH2*2 的激活剂 Alda-1 在体外和体内减弱了乙醇诱导的 Aβ 增加和神经炎症。这些数据表明醛的代谢受损，特别是乙醇衍生的乙醛，