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.

项目概要/摘要 焦虑和抑郁在酒精使用障碍 (AUD) 和阿尔茨海默病中同时出现，并且这两种疾病 针对海马和杏仁核的去甲肾上腺素能系统和回路。这种症状和症状的重叠 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 暴露会使大脑走上一条更容易受到阿尔茨海默病和相关疾病影响的轨迹 老年痴呆症。相互矛盾的文献表明，轻度至中度饮酒可能具有保护作用，而其他文献则表明 报告饮酒和 AD 风险增加的风险或没有影响。饮酒的持续时间和强度各不相同 痴呆症的测量可能导致对酒精相互作用缺乏一致的理解 阿尔茨海默病的暴露和发展。临床前模型和良好对照研究的使用将 提供一个平台来了解可能的重叠机制，这些机制可以在重大事件之后触发 AD 青春期接触乙醇。令人惊讶的是，迄今为止，很少有临床前研究调查过 饮酒与 AD 风险和疾病进展之间的相互作用。支持澳元的假设 增强 AD 病理学，最近一项在 3xFAD 小鼠中使用青少年间歇性乙醇暴露 (P25-55) 的研究 携带三种人类 AD 突变的海马、杏仁核和脑组织中 Aβ1-42 的积累增加 成年女性内嗅皮层和海马体中 pTau 的积累。这些老鼠也经历了 焦虑加剧以及学习和记忆缺陷。重要的是，通过药理学阻断炎症 阻止了病理和行为的改变。在另一项针对 pTau 突变小鼠人源化的研究中， 间歇性乙醇增加蓝斑（LC）去甲肾上腺素能神经元的兴奋性，效果最佳 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 功能障碍并缩短前驱期 AD 的时间。目标 1 将检验 AIE 暴露的假设 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 TgF344-AD 大鼠的前驱 AD。目标 2 将检验 AIE 暴露加速赤字的假设 成人 AD 前驱阶段的学习和记忆、增加焦虑并损害恐惧消退 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 研究结果将作为未来机制研究的启动平台。