Chronic Alcohol Exposure and Pathophysiology of Alzheimer's Disease.

项目摘要 众所周知，反复和过度饮酒会导致脑损伤，并可能增加风险 阿尔茨海默病（AD）的发病率。最近的一项研究表明，轻度至中度酒精 饮酒量低至每周8杯，可能与认知能力下降和AD有关。不 令人惊讶的是，饮酒似乎对老年人的危害更大。由于酒精代谢 随着年龄的增长，它可能会产生更大的影响，并可能加剧潜在的认知问题。 然而，这些流行病学研究的局限性包括它们的观察性质， 对酒精如何影响AD发展的“因果关系”的机制研究。 重要的是，众所周知，女性患AD的可能性大约是男性的两倍。然而，在这方面， AD性别特异性差异的遗传学和生物学基础尚不清楚。因此必须 为了了解酒精在多大程度上会加剧AD的发展， 饮酒年龄、性别和遗传风险因素。基于对酒精使用的深入研究 疾病（AUD）（Dr. Choi）和AD（Dr. Trushina），两名PI建议进行合作研究 采取综合办法解决这些基本问题。使用两个小鼠模型 代表家族性AD（APP/PS1）和迟发性散发性AD（ApoE 4KI），我们将研究是否 酒精暴露具有性别和/或年龄依赖性效应，可加重AD的发作和发展， 处于危险中的人。为了研究这一假设，我们提出了两个具体目标。在第一个目标中，我们将 确定慢性酒精暴露是否会加重AD样行为和代谢表型， APP/PS1和ApoE 4KI小鼠模型。在第二个目标中，我们将确定慢性酒精的影响 暴露对AD的病理生理学和生物标志物的影响。结果将是重大的， 全面的数据和关键的生物学证据，以建立临床前标准， 关于酒精对AD的影响的可翻译信息。

Project Summary Repeated and excessive alcohol consumption is known to lead to brain damage, and may increase the risk of developing Alzheimer’s Disease (AD). A recent study demonstrated that light-to-moderate alcohol consumption, as low as eight drinks a week, may be associated with cognitive decline and AD. Not surprisingly, alcohol consumption appears to be more harmful to the elderly. Since alcohol metabolism rates decline with age, it could have a greater effect and may exacerbate underlying cognitive problems. However, the limitation of these epidemiological studies includes their observational nature without a mechanistic investigation of the “cause and effect” on how alcohol may impact the AD development. Importantly, it is widely known that women are approximately twice as likely to develop AD. However, genetic and biological basis of the sex specific differences in AD is understudied. Therefore, it is essential to understand to what extent alcohol could exacerbate the development of AD depending on the starting age of alcohol consumption, sex, and genetic risk factors. Based on the in-depth expertise in alcohol use disorder (AUD) (Dr. Choi) and AD (Dr. Trushina), two PIs propose to conduct a collaborative research applying comprehensive approach to address these fundamental questions. Using two mouse models representing familial AD (APP/PS1) and late-onset sporadic AD (ApoE4KI), we will examine whether alcohol exposure has sex and/or age-dependent effect exacerbating the onset and development of AD in at-risk individuals. To investigate this hypothesis, we propose two specific aims. In the first aim, we will determine whether chronic alcohol exposure exacerbates AD-like behavioral and metabolic phenotype in APP/PS1 and ApoE4KI mouse models. In the second aim, we will determine the impact of chronic alcohol exposure on the pathophysiology and biomarkers of AD. The outcomes will be significant providing comprehensive data and critical biological evidence to establish the preclinical criteria and provide translatable information regarding the impact of alcohol on AD.