Adolescent Alcohol Abuse, PTSD and Alzheimer's Disease Administrative Supplement

项目摘要/摘要 焦虑和抑郁同时出现在酒精使用障碍(AUD)和阿尔茨海默病中，这两种疾病 目标是去甲肾上腺素系统和海马区和杏仁体的环路。这种症状和症状重叠 受影响的大脑区域提出了共享机制的问题，以及青少年间歇性饮酒是否 暴露会使大脑进入一个更容易受到阿尔茨海默氏症病理和相关疾病影响的轨道 老年痴呆症。相互矛盾的文献表明，轻度到中度饮酒可能是有保护作用的，而其他一些 报告酒精使用和AD风险增加的风险或没有影响。不同的饮酒持续时间和强度以及 痴呆症的衡量标准可能导致对酒精相互作用缺乏连贯的理解 阿尔茨海默病的暴露和发展。使用临床前模型和良好控制的研究将 提供一个平台，以了解可能的重叠机制，这些机制可能会在重大事件后触发AD 青春期接触酒精。令人惊讶的是，到目前为止，极少的临床前研究 酒精使用与AD风险和疾病进展之间的相互作用。支持这样的假设：澳元 加强AD病理，最近一项使用青少年间歇性酒精暴露(P25-55)在3xFAD小鼠中的研究 存在三个人类AD突变的人显示，Aβ1-42在海马区、杏仁体和 成年女性海马区内嗅皮层和ptau的蓄积。这些小鼠还经历了 增加焦虑，学习和记忆缺陷。重要的是，从药理上来说，它可以阻断炎症 预防病理改变和行为改变。在另一项关于人源化ptau突变小鼠的研究中， 间歇性乙醇增强蓝斑去甲肾上腺素能神经元兴奋性的作用最强 在雌性身上。我们在AUD、AD、性别差异和突触回路方面的专业知识巧妙而独特地使我们能够 测试青春期间歇性酒精加速AD病理和突触的总体假设 功能障碍，缩短AD前驱病程。目标1将检验AIE暴露的假设 加速抗体和ptau的积累，增加胶质增生以及神经元和突触功能障碍 成年TgF344-AD大鼠的前驱性AD。目标2将检验以下假设：AIE暴露会加速脑部疾病的发生 在成人阿尔茨海默病的前驱阶段，学习和记忆增加焦虑，损害恐惧消退 TgF344-AD大鼠。这些研究将提供有关AUD和AD相互作用的基础信息 这些发现将作为未来机械学研究的发射台。

PROJECT SUMMARY/ABSTRACT Anxiety and depression co-occur in both alcohol use disorder (AUD) and Alzheimer’s disease, and both illnesses target the noradrenergic system and circuits in hippocampus and amygdala. This overlap in symptoms and impacted brain regions raise the question of shared mechanisms, and whether adolescent intermittent ethanol exposure can set the brain on a trajectory that makes it more susceptible to Alzheimer’s pathology and related dementia in aging. Conflicting literature shows light to moderate alcohol drinking may be protective, while others report increased risk, or no effect, of alcohol use and AD risk. Variable durations and intensity of alcohol use and measures of dementia likely contribute to the lack of a coherent understanding of the interactions of alcohol exposure and development of Alzheimer’s disease. Use of preclinical models and well controlled studies will provide a platform to understand possible overlapping mechanisms that can trigger AD following significant ethanol exposure during adolescence. Surprisingly, to date, extremely few preclinical studies have investigated the interaction between alcohol use and AD risk and disease progression. In support of the hypothesis that AUD augments AD pathology, a recent study using adolescent intermittent ethanol exposure (P25-55) in 3xFAD mice harboring three human AD mutations displayed increased Aβ1–42 accumulation in hippocampus, amygdala, and entorhinal cortex and pTau accumulation in hippocampus of adult females. These mice also experienced increased anxiety and learning and memory deficits. Importantly, pharmacologically blocking inflammation prevented both the pathological and behavioral changes. In another study in humanize pTau mutant mice, intermittent ethanol increased excitability of locus coeruleus (LC) noradrenergic neurons with a greatest effect in females. Our expertise in AUD, AD, sex differences and synaptic circuits skillfully and uniquely positions us to test the overarching hypothesis that adolescent intermittent ethanol accelerates AD pathology and synaptic dysfunction and shortens the period of prodromal AD. Aim 1 will test the hypothesis that AIE exposure accelerates accumulation of Ab and pTau and increases gliosis and neuronal and synaptic dysfunction during prodromal AD in adult TgF344-AD rats. Aim 2 will test the hypothesis that AIE exposure accelerates deficits in learning and memory, increases anxiety, and impaires fear extinction during the prodromal phase of AD in adult TgF344-AD rats. These studies will provide foundational information regarding the interaction of AUD and AD and the findings will serve as a launch pad for future mechanistic studies.