Alcohol and the Serotonin System in the Progression of AlzheimerÂs Disease

酒精和血清素系统在阿尔茨海默氏病进展中的作用

基本信息

批准号：
10456983
负责人：
Catherine Anne Marcinkiewcz
金额：
$ 38.63万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456983
关键词：
3-Dimensional Adoptive Transfer Age of Onset Aging Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Anxiety Area Attention Behavior Brain Brain region Chronic Chronic Insomnia Clinical Cognitive deficits Data Dementia Disease Distal Dorsal Early Intervention Elderly Electroencephalography Electrophysiology (science)Exhibits Exposure to Fiber Goals Hippocampus (Brain)Homeostasis Human Image Impaired cognition Investigation Lead Light Link Literature Memory impairment Microglia Mus Nerve Degeneration Neurofibrillary Tangles Neurons Pathogenesis Pathology Photometry Play Process Property Protein Isoforms Recording of previous events Research Role Seeds Serotonergic System Serotonin Sleep Sleep Deprivation Sleep disturbances Sleeplessness Synapses Techniques Viral Vector Work alcohol effect alcohol exposure alcohol use disorder base chronic alcohol ingestion cognitive development depressive symptoms designer receptors exclusively activated by designer drugs dorsal raphe nucleus entorhinal cortex exposed human population in vivo insight neurofibrillary tangle formation neuroinflammation neuromechanism neuropathology new therapeutic target non rapid eye movement relating to nervous system restoration synergism tau Proteins tau aggregation

项目摘要

Project Summary / Abstract Alcohol use disorders (AUDs) are associated with neurodegeneration and cognitive dysfunction, but the impact of alcohol use on Alzheimer's disease and related dementias (ADRD) is unknown. Our work suggests that chronic alcohol can alter the activity of serotonin (5-HT) neurons in the DRN, which may cause disruption in sleep homeostasis in the early stages of ADRD. Both AUD and ADRD are associated with chronic insomnia, but to date no studies have linked alcohol-induced sleep disturbances to tau-based neuropathology in the brain. Sleep disruption also induces microglial activation and aging, which can promote the spread of tau pathology in the brain. In Aim 1, we will use EEG, fiber photometry, electrophysiology and DREADD-based manipulations of neural activity in vivo in mice expressing human tau pathology (htau mice) to determine whether chronic alcohol exacerbates sleep deficits and whether enhanced neural activity in 5-HT neurons contributes to sleep disruptions. In Aim 2, we will examine the effect of chronic alcohol on microglia and their contribution to the progression of tau pathology in the DRN. In Aim 3, we will determine whether chronic alcohol can facilitate the spread of tau pathology from the DRN to other brain regions using an AAV-based strategy for expressing tau pathology exclusively in 5-HT neurons. 3D immunolabeling and light sheet imaging using the iDISCO technique will be used to identify areas and quantify the extent of tau spread. We will also examine whether neural activity in 5-HT neurons and microglial activation contributes to this spread. In total, the proposed research will provide mechanistic insight into the impact of chronic alcohol on early accumulation and spread of tau pathology in the brain and the later development of cognitive and memory deficits.

项目概要/摘要酒精使用障碍 (AUD) 与神经退行性变和认知功能障碍有关，但其影响饮酒对阿尔茨海默病和相关痴呆症 (ADRD) 的影响尚不清楚。我们的工作表明长期饮酒会改变 DRN 中血清素 (5-HT) 神经元的活性，这可能会导致 ADRD 早期阶段的睡眠稳态。 AUD 和 ADRD 都与慢性失眠有关，但迄今为止，尚无研究将酒精引起的睡眠障碍与大脑中基于 tau 的神经病理学联系起来。睡眠中断还会诱导小胶质细胞激活和衰老，从而促进 tau 蛋白病理学的传播大脑。在目标 1 中，我们将使用脑电图、纤维光度测定、电生理学和基于 DREADD 的操作表达人类 tau 病理学的小鼠（htau 小鼠）的体内神经活动以确定是否患有慢性酒精加剧睡眠不足以及 5-HT 神经元的神经活动增强是否有助于睡眠干扰。在目标 2 中，我们将研究长期饮酒对小胶质细胞的影响及其对 DRN 中 tau 病理学的进展。在目标 3 中，我们将确定长期饮酒是否可以促进使用基于 AAV 的 tau 表达策略将 tau 病理从 DRN 传播到其他大脑区域病理学仅存在于 5-HT 神经元中。使用 iDISCO 技术进行 3D 免疫标记和光片成像将用于识别区域并量化 tau 扩散的程度。我们还将检查神经活动是否 5-HT 神经元和小胶质细胞的激活有助于这种传播。总的来说，拟议的研究将提供深入了解慢性酒精对 tau 病理学早期积累和传播影响的机制大脑以及随后的认知和记忆缺陷的发展。