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

基本信息

批准号：
10706467
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
项目类别：
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/10706467
关键词：
Accounting Address Affect Affective Age Alcohol consumption Alcohol dependence Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos 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 Synapses 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

项目摘要

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.

项目概要/摘要阿尔茨海默病 (AD) 是全世界最常见的神经退行性疾病，占大约一半到三分之二的痴呆症病例与认知障碍和认知障碍有关。此外，β-淀粉样斑块（Aβ）沉积物的增加与酒精使用障碍（AUD）有关。神经退行性变和认知障碍，但酒精依赖对 AD 的作用已在一定程度上得到了证实。最近的证据表明，饮酒可能是酒精中毒发病和严重程度的一个危险因素。然而，鉴于酒精的普遍使用，阿尔茨海默病的总体报告好坏参半，这一点至关重要。为了了解饮酒对 AD 的潜在影响，我们将研究饮酒史的影响。依赖于与 AD 相关的行为和神经病理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 中的神经网络功能。或不使用美金刚治疗可以逆转行为和神经病理症状。酒精依赖史会导致 AD 小鼠及早出现认知障碍存在更多的 Aβ 沉积物，这些缺陷可以通过美金刚的长期治疗来弥补。我们发现 AD 小鼠的酒精依赖史会改变网络连接（减少模块化和改变中心区域），并且这些影响将通过美金刚治疗得到缓解。由酒精依赖引起的功能网络连接的影响将在小鼠模型中进行评估 AD. 这些变化将与 Aβ 沉积物在大脑中的分布进行比较，这将表明 Aβ 沉积的方式。 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，酒精依赖在 AD 中的作用（例如，网络连接和行为的变化以及将使用 AUD 的相关临床前转化模型进行检查。将评估 AD 和野生型饮酒者的功能、焦虑样行为和烦躁样行为将评估AD小鼠中Aβ沉积物的数量和位置的差异。 AD 和野生型小鼠的网络连接将使用层次聚类和图论进行检查。发现酒精依赖会影响 AD 的神经和行为症状的发作，那么这将这是一项非常重要的发现，将对临床前和临床研究产生广泛影响。研究结果还可能直接影响公共饮酒指南，特别是对于那些有家族史的人 AD 风险。