Chronic Alcohol Exposure and Pathophysiology of Alzheimer's Disease.

项目摘要 众所周知，反复过量饮酒会导致大脑损伤，并可能增加患病风险。 罹患阿尔茨海默病(AD)的风险。最近的一项研究表明，轻度到中度酒精 每周低至8杯的饮酒量可能与认知能力下降和阿尔茨海默病有关。不 令人惊讶的是，饮酒似乎对老年人的伤害更大。因为酒精代谢 发病率随着年龄的增长而下降，这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，而不是 对酒精如何影响阿尔茨海默病发展的“因果关系”进行机械调查。 重要的是，众所周知，女性患阿尔茨海默病的可能性大约是女性的两倍。然而， 阿尔茨海默病性别特异性差异的遗传和生物学基础尚未得到充分研究。因此，它是必不可少的 了解酒精在多大程度上会加剧阿尔茨海默病的发展，这取决于开始 饮酒年龄、性别和遗传危险因素。基于对酒精使用的深入专业知识 障碍(AUD)(Choi博士)和AD(Trushina博士)，两位PI建议进行一项合作研究 运用综合方法解决这些根本问题。使用两种鼠标模型 代表家族性AD(APP/PS1)和晚发性散发性AD(ApoE4KI)，我们将检查 酒精暴露具有性别和/或年龄依赖性效应，加剧了AD的发生和发展 高危人群。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剧AD样行为和代谢表型 APP/PS1和ApoE4KI鼠标型号。在第二个目标中，我们将确定慢性酒精的影响 暴露于阿尔茨海默病的病理生理和生物标志物。结果将是显著的，如果 全面的数据和关键的生物学证据，以建立临床前标准并提供 关于酒精对AD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.