4/8: INIA Stress and Chronic Alcohol Interactions: Impact of stress mediated locus coeruleus dysregulation on cognitive control and excessive drinking

项目总结 酗酒史和压力史都会增加患阿尔茨海默病的风险 相关痴呆症，包括早发性痴呆症。我们认为，高酒精摄入量有助于 阿尔茨海默病的发病或加重阿尔茨海默病的病理，特别是在脑干核团 蓝斑(LC)。定义阿尔茨海默病与病理相关的哪些方面的基础研究 是由酒精驱动的，以及是如何驱动的，目前仍不清楚。导致阿尔茨海默病的病理变化 已知在症状出现前几十年就会发生。中枢神经系统最早的变化之一 在LC中tau蛋白过度磷酸化和细胞功能障碍。LC病理是一种普遍存在的后遗症。 致命的阿尔茨海默病。鉴于LC病理和散发性之间已建立的关系 阿尔茨海默病，在LC内促进病理的药物可能会增加阿尔茨海默病的风险。在我们的父母身上 如果我们观察酒精和压力对幼年动物LC功能的影响，我们已经确定 大量饮酒的小鼠和猴子也表现出认知功能障碍。本补充文件的目标是 研究酒精和压力史是如何导致阿尔茨海默氏症的 中年动物的病理学。我们的中心假设是，饮酒量增加是对酒精和 应激史也促进了LC中早发性阿尔茨海默氏样病理的发生。我们将对这一假设进行评估 使用啮齿动物和非人类灵长类动物的性别和物种。我们将调查两国之间的关系 酒精剂量、认知改变和阿尔茨海默病样病理在LC。我们会比较年龄- 将对照组与酒精和压力暴露的动物相匹配，并观察酒精摄入量的个体差异， 认知与阿尔茨海默氏症的相关病理。将使用一组组织病理学标志物来评估LC 完整性，测量氧化应激，自噬，细胞凋亡，过度磷酸化tau，肾上腺素能受体 不同酒精剂量猕猴和小鼠LC的表达及无偏体视学计数 历史。在这两个物种中，我们将分析先前的酒精摄入量、认知和 病理学，以确定指示阿尔茨海默氏样病理风险的行为预测因素。这些目标将 回答有关饮酒和阿尔茨海默病之间关系的紧迫问题。跨物种 从人类阿尔茨海默病样本中反向翻译的分析和标记增强了我们的临床相关性 调查结果。我们的结果将为未来阿尔茨海默病的诊断和早期干预策略提供参考 酒精使用障碍的背景。

PROJECT SUMMARY A history of heavy alcohol and a history of stress both independently increase the risk of Alzheimer's disease related dementia, including early onset dementia. We propose that high alcohol consumption facilitates the onset of, or exacerbates the severity of, Alzheimer's disease pathology specifically in the brainstem nucleus locus coeruleus (LC). The basic research that defines which aspects of Alzheimer's disease related pathology are driven by alcohol and how, remains unknown. The pathological changes that lead to Alzheimer's disease are known to occur decades before symptoms arise. One of the earliest changes in the central nervous system is tau hyperphosphorylation and cellular dysfunction within LC. LC pathology is a ubiquitous finding of post- mortem Alzheimer's disease. Given the established relationship between LC pathology and sporadic Alzheimer's disease, agents that promote pathology within LC likely promote Alzheimer's risk. In our parent grant we look at the impact of alcohol and stress on LC function in young animals, we have established that high alcohol drinking mice and monkeys also demonstrate cognitive dysfunction. The goal of this supplement is to investigate how alcohol and stress history that drives elevated drinking contributes to Alzheimer's related pathology in middle aged animals. Our central hypothesis is that elevated drinking in response to alcohol and stress history also promotes early onset Alzheimer's-like pathology in the LC. We will evaluate this hypothesis across sexes and species using rodents and non-human primates. We will investigate the relationship between alcohol dose, changes in cognition and Alzheimer's disease-like pathology in LC. We will compare age- matched controls to alcohol and stress exposed animals and look at individual differences in alcohol intake, cognition and Alzheimer's related pathology. A histopathological battery of markers will be used to evaluate LC integrity, measuring oxidative stress, autophagy, apoptosis, hyperphosphorylated tau, adrenergic receptor expression and unbiased stereological counts of LC from macaques and mice with varying alcohol dose histories. In both species we will analyze the relationship between prior alcohol intake, cognition, and pathology to identify behavioral predictors indicative of risk for Alzheimer's-like pathology. These aims will answer pressing questions on the relationship between alcohol intake and Alzheimer's disease. Cross-species analysis and markers back translated from human Alzheimer's samples enhance the clinical relevance of our findings. Our results will inform future diagnostic and early intervention strategies for Alzheimer's disease in the context of alcohol use disorder.