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

青少年酒精滥用、创伤后应激障碍和阿尔茨海默病行政补充

• 批准号: 10715295
• 负责人: L Judson Chandler
• 金额: $ 37.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10715295
• 关键词: APP-PS1; Acceleration; Acute; Address; Administrative Supplement; Adolescent; Adult; Age Months; Aging; Alcohol abuse; Alcohol consumption; Alcohols; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amygdaloid structure; Animal Model; Anxiety; Behavior; Behavioral; Brain; Brain Pathology; Brain region; Cognitive deficits; Complement; Controlled Study; Cues; Dementia; Development; Disease; Disease Progression; Electrophysiology (science); Encephalitis; Ethanol; Exhibits; Extinction; Female; Fright; Functional disorder; Future; Genetic; Gliosis; Goals; Health; Hippocampus; Human; Immunohistochemistry; Impaired cognition; Inflammation; Knowledge; Learning; Light; Link; Literature; Longevity; Maintenance; Measures; Medial; Memory; Memory impairment; Mental Depression; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neuroimmune; Neurons; Onset of illness; Pathologic; Pathology; Phase; Physiological; Positioning Attribute; Post-Traumatic Stress Disorders; Pre-Clinical Model; Predisposition; Process; Rattus; Reporting; Research Personnel; Risk; Risk Factors; Role; Sex Differences; Signal Transduction; Slice; Suggestion; Symptoms; Synapses; Synaptic plasticity; System; Testing; Time; Tissues; Transgenic Organisms; Western Blotting; adolescent alcohol abuse; adolescent alcohol exposure; age related; alcohol exposure; alcohol research; alcohol use disorder; axonal degeneration; behavioral study; brain circuitry; conditioned fear; design; early onset; entorhinal cortex; epidemiology study; experience; experimental study; granule cell; improved; interest; locus ceruleus structure; male; neural circuit; neuroinflammation; neuronal circuitry; neuronal excitability; neurotransmission; noradrenergic; novel; object recognition; parent grant; pharmacologic; preclinical study; prevent; prodromal Alzheimer' s disease; receptor; sex; underage drinking

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.

项目总结/摘要 焦虑和抑郁同时发生在酒精使用障碍（AUD）和阿尔茨海默病中，这两种疾病 靶向去甲肾上腺素能系统和海马体和杏仁核中的回路。这种症状的重叠， 受影响的大脑区域提出了共享机制的问题，以及青少年间歇性乙醇是否 暴露可以使大脑处于一种轨道上，使其更容易患上阿尔茨海默病和相关疾病。 老年痴呆症研究文献显示，轻度至中度饮酒可能具有保护作用，而其他人则认为， 报告饮酒和AD风险增加或无影响。酒精使用的持续时间和强度不同， 痴呆症的测量可能导致对酒精的相互作用缺乏连贯的理解， 暴露和发展阿尔茨海默病。使用临床前模型和良好对照研究将 提供了一个平台，以了解可能的重叠机制，可以触发AD以下重大 青春期的酒精暴露令人惊讶的是，迄今为止，很少有临床前研究调查了 酒精使用与AD风险和疾病进展之间的相互作用。为了支持澳元的假设， 增强AD病理学，最近的一项研究在3xFAD小鼠中使用青少年间歇性乙醇暴露（P25-55） 携带三种人类AD突变的人显示海马、杏仁核和海马中Aβ1-42蓄积增加， 内嗅皮质和成年雌性海马中的pTau积累。这些老鼠也经历了 增加焦虑和学习记忆缺陷。重要的是， 阻止了病理和行为的改变。在另一项人源化pTau突变小鼠的研究中， 间歇性乙醇增加蓝斑去甲肾上腺素能神经元的兴奋性， 在女性中。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 测试青少年间歇性乙醇加速AD病理和突触的总体假设 缩短AD前驱期。目标1将检验AIE暴露 加速Ab和pTau的积累，并增加神经胶质增生以及神经元和突触功能障碍， 成年TgF 344-AD大鼠的前驱AD。目标2将检验AIE暴露加速以下缺陷的假设： 在成人AD的前驱期，学习和记忆，增加焦虑，并损害恐惧消退 TgF 344-AD大鼠。这些研究将提供关于AUD和AD相互作用的基础信息 这一发现将作为未来机理研究的起点。