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.

项目摘要 /摘要 阿尔茨海默氏病（AD）是全球最常见的神经退行性疾病 所有痴呆症病例的大约一半到三分之二。它与认知障碍和 β-淀粉样菌斑（Aβ）沉积物的增加。此外，酒精使用障碍（AUD）与 神经变性和认知障碍，但酒精依赖对AD的作用有些有些 有争议的。最近的证据表明，酒精使用作为危险因素的发作和严重程度可能起作用 阿尔茨海默氏病，但是总体报道已混杂。考虑到无处不在的酒精，这是至关重要的 了解饮酒对AD的潜在影响。我们将研究酒精史的影响 对与AD相关的行为和神经病理症状的发作和严重程度的依赖。我们 将进一步研究酒精依赖性如何影响AD中的神经网络功能。我们将评估是否 或者不使用美灵治疗可以扭转行为和神经病理学症状。我们假设 酒精依赖的史将导致AD小鼠的认知障碍早期发作 较大的Aβ沉积物的存在，这些缺陷将通过纪念慢性治疗来挽救。 我们假设AD小鼠的酒精依赖史将改变网络连通性（降低） 模块化和更改枢纽区域），这些影响将通过美容治疗来缓解。改变 酒精依赖引起的功能网络连通性将在小鼠模型中评估 广告。这些变化将与Aβ沉积物的大脑范围扩散进行比较，这将表明在 AD会影响脑部范围的功能，并可能超出大脑区域，并具有神经病理学的迹象。此外， 酒精依赖性在AD中的作用（例如，网络连通性和行为的变化以及 神经病理症状）将使用AUD的相关翻译临床前模型检查。认知的 功能，类似动画的行为和类似烦躁的行为将在AD和WildType饮酒中进行评估 和酒精幼稚的小鼠。 Aβ沉积物的数量和位置将评估AD小鼠。差异 AD和WildType小鼠中的网络连接将使用层次聚类和图形论进行检查。如果 发现酒精依赖性会影响AD的神经系统和行为症状的发作，这将 成为一个非常重要的发现，将对临床前和临床研究产生广泛影响。这些潜力 调查结果也可能直接影响公共饮酒准则，尤其是在有家庭的人中 AD风险。