Identifying the relationship between alcohol and Alzheimer's Disease

确定酒精与阿尔茨海默病之间的关系

• 批准号: 10412429
• 负责人: Adam J Kimbrough
• 金额: $ 34.33万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412429
• 关键词: Accounting; Address; Affect; Affective; Age; Alcohol consumption; Alcohol dependence; Alcohols; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Area; Behavior; Behavioral; Behavioral Symptoms; Brain; Brain region; Cells; Chronic; Clinical Research; Cognitive; Cognitive deficits; Consumption; Data; Dementia; Deposition; Emotional; Ethanol; Functional disorder; Guidelines; Heavy Drinking; Human; Impaired cognition; Incidence; Individual; Injections; Location; Measures; Memantine; Mus; NMDA receptor antagonist; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Symptoms; Neurons; Pre-Clinical Model; Preventive measure; Preventive treatment; Process; Recording of previous events; Reporting; Risk Factors; Role; Saline; Senile Plaques; Severities; Stains; Structure; Symptoms; Testing; Tissues; Transgenic Mice; Treatment Effectiveness; Wild Type Mouse; alcohol effect; alcohol research; alcohol use disorder; anxiety-like behavior; associated symptom; cognitive function; cognitive testing; cohort; design; drinking; early onset; effective therapy; experimental study; graph theory; morris water maze; mouse model; neural network; neuropathology; novel; object recognition; pre-clinical research; reduce symptoms; targeted treatment; therapeutic development; treatment guidelines; treatment strategy; vapor; young adult

Project Summary / Abstract Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, accounting for approximately half to two-thirds of all cases of dementia. It is associated with cognitive impairments and an increase in β-amyloid plaque (Aβ) deposits. Moreover, alcohol use disorder (AUD) has been associated with neurodegeneration and cognitive impairments, but the role of alcohol dependence on AD has been somewhat controversial. Recent evidence suggests a likely role for alcohol use as a risk factor in onset and severity of Alzheimer's disease, however overall reports have been mixed. Given the pervasive use of alcohol, it is critical to understand the potential impact of alcohol drinking on AD. We will examine the impact of a history of alcohol dependence on the onset and severity of behavioral and neuropathological symptoms associated with AD. We will further examine how alcohol dependence influences neural network function in AD. We will assess whether or not treatment with Memantine can reverse the behavioral and neuropathological symptoms. We hypothesize that a history of alcohol dependence will result in an earlier onset of cognitive impairment in AD mice as well as a greater presence of Aβ deposits and that these deficits will be rescued by chronic treatment with Memantine. We hypothesize that a history of alcohol dependence in AD mice will alter network connectivity (decrease modularity and change hub regions) and that these effects will be alleviated by Memantine treatment. Alterations of functional network connectivity that are caused by alcohol dependence will be assessed in a mouse model of AD. These changes will be compared with the brain-wide spread of Aβ deposits, which will indicate the way in which AD affects brain-wide function, potentially beyond brain areas with signs of neuropathology. Furthermore, the role of alcohol dependence in AD (e.g., changes in network connectivity and behavioral and neuropathological symptoms) will be examined using a relevant translational preclinical model of AUD. Cognitive function, anxiety-like behavior, and irritability-like behavior will be assessed in AD and wildtype alcohol drinking and alcohol naive mice. The number and location of Aβ deposits will be assessed AD mice. Differences in network connectivity in AD and wildtype mice will be examined using hierarchical clustering and graph theory. If alcohol dependence is found to impact the onset of neurological and behavioral symptoms of AD, then this will be a highly significant finding that will have a broad impact on preclinical and clinical research. These potential findings may also directly influence public guidelines for alcohol consumption, especially in those with a familial risk for AD.

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是世界范围内最常见的神经退行性疾病， 大约一半到三分之二的痴呆病例。它与认知障碍有关， β-淀粉样斑块（Aβ）沉积增加。此外，酒精使用障碍（AUD）与 神经退行性疾病和认知障碍，但酒精依赖对AD的作用已经有点 争议最近的证据表明，酒精使用可能是一个危险因素，在发病和严重程度， 然而，阿尔茨海默病的总体报告喜忧参半。鉴于酒精的普遍使用， 了解饮酒对AD的潜在影响。我们将研究酒精史的影响 依赖于与AD相关的行为和神经病理学症状的发作和严重程度。我们 将进一步研究酒精依赖如何影响AD的神经网络功能。我们将评估是否 无论是否使用美金刚治疗，都可以逆转行为和神经病理学症状。我们假设 酒精依赖史将导致AD小鼠认知障碍的早期发作， Aβ沉积物的存在更大，并且这些缺陷将通过美金刚胺的长期治疗来挽救。 我们假设AD小鼠的酒精依赖史会改变网络连接（减少）， 模块化和改变枢纽区域），并且这些影响将通过美金刚胺处理减轻。改变 由酒精依赖引起的功能性网络连接将在小鼠模型中进行评估， AD.这些变化将与Aβ沉积物在全脑的扩散进行比较，这将表明A β沉积物进入大脑的方式。 AD影响全脑功能，可能超出具有神经病理学迹象的大脑区域。此外，委员会认为， 酒精依赖在AD中的作用（例如，网络连接和行为的变化， 神经病理学症状）将使用AUD的相关转化临床前模型进行检查。认知 将在AD和野生型饮酒中评估功能、焦虑样行为和易怒样行为 和未接触过酒精的小鼠。将在AD小鼠中评估Aβ沉积物的数量和位置。差异 AD和野生型小鼠中的网络连接性将使用分级聚类和图论来检查。如果 酒精依赖被发现会影响AD的神经和行为症状的发作，那么这将 这是一个非常重要的发现，将对临床前和临床研究产生广泛的影响。这些潜在 研究结果也可能直接影响公众对酒精消费的指导，特别是在那些有家族遗传病的人中。 AD的风险