Inflammasome activation in modulation of Alzheimer's Disease by alcohol

酒精调节阿尔茨海默氏病中炎症小体的激活

基本信息

批准号：
10673213
负责人：
Douglas T Golenbock
金额：
$ 42.81万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673213
关键词：
APP-PS1 Acceleration Affect Age Months Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Behavioral Biochemical Biology Brain Brain Injuries CASP1 gene Chronic Cognitive Dementia Deposition Development Diet Disease Progression Elements Encephalitis Enzyme-Linked Immunosorbent Assay Gene Expression Heavy Drinking Immune signaling Impaired cognition Inflammasome Inflammation Inflammatory Interleukin-1 Interleukin-1 Receptors Interruption Intervention Long-Term Effects Long-Term Potentiation Mediating Messenger RNA Microglia Modeling Molecular Morphology Multiprotein Complexes Mus Neuronal Dysfunction Neurons Organ Pathogenesis Pathogenicity Pathology Pathway interactions Play Production Proteins Reporting Research Role Signal Pathway Signal Transduction Testing Vertebral column Water Western Blotting alcohol effect alcohol exposure alcohol response anakinra antagonist brain tissue chronic alcohol ingestion cytokine drinking water epidemiologic data experimental study feeding insight mouse model neuroinflammation novel pharmacologic pre-clinical protein complex tau Proteins tau-1 therapeutic target

项目摘要

Neuroinflammation has emerged as a critical feature of Alzheimer’s disease (AD) pathogenesis and alcohol-related brain damage. Previous studies, including our own, have shown that innate immune signaling pathways particularly NLRP3 inflammasome activation play an important role both in AD and in alcohol-induced neuroinflammation. However, the influence of heavy alcohol use on AD remains largely unknown. The focus of our research is to evaluate the effect of excessive alcohol consumption on the development and progression of AD and identify critical molecular pathways that may provide therapeutic targets. Activation of the multiprotein complex, inflammasome, by PAMPs or DAMPs involves two signals: first, TLR-mediated activation that increases pro-IL-1ß and second, NLRP-mediated inflammasome assembly and caspase-1 activation that cleaves pro- IL-1ß to mature IL-1ß. We previously showed increased IL-1ß production as a result of NLRP3/ASC inflammasome and caspase-1 activation in the brain after chronic alcohol feeding. In the APP/PS1 and Tau22 mouse models of AD, caspase-1 activity and IL-1ß production is dependent on NLRP3 and NLRP3 inflammasome activation drives Aß and tau pathology. Based on these observations, we hypothesize that chronic alcohol exposure accelerates and exacerbates AD features. We postulate that chronic alcohol-induced NLRP3/ASC inflammasome activation contributes to the development and progression of AD via amplified neuroinflammation. The aims of this study are 1. To characterize the effect of long-term and excessive alcohol consumption on AD features using APP/PS1 and Tau22 mice 2. To delineate the role of NLRP3/ASC inflammasome components in alcohol-mediated neuroinflammation in AD mice 3. To evaluate the contribution of IL-1 signaling pathway in inflammasome-mediated neuroinflammation in response to alcohol consumption in AD mice. These experiments will provide novel insight on the role of alcohol-mediated inflammasome activation in the development and progression of AD and evaluate preclinical interventions that interrupt inflammasome-mediated neuroinflammation by targeting key pathogenic pathways discovered in this research.

神经炎症已成为阿尔茨海默氏病（AD）发病机理的关键特征和与酒精有关的脑损伤。以前的研究，包括我们自己的研究，已经表明了天生免疫信号通路特别是NLRP3炎性体激活起着重要作用在AD和酒精引起的神经炎症中。但是，大量酒精的影响在广告上的使用仍然很大未知。我们研究的重点是评估过度饮酒在AD的开发和发展中，并确定关键可以提供治疗靶标的分子途径。多蛋白复合物的激活，炎症小体，通过大型或潮湿涉及两个信号：首先，TLR介导的激活，即增加pro-il-1ß和第二个NLRP介导的炎性体组装和caspase-1 将pro-il-1ß切割至成熟的IL-1ß的激活。我们以前显示IL-1ß增加由于NLRP3/ASC炎症体和大脑中的caspase-1激活而产生慢性酒精喂养。在App/ps1和Tau22 AD的鼠标模型中，caspase-1活性和 IL-1ß产生取决于NLRP3和NLRP3炎性体激活驱动Aß和TAU 病理。基于这些观察结果，我们假设慢性酒精暴露加速并加剧广告功能。我们假设慢性酒精引起 NLRP3/ASC炎性体激活有助于通过扩增神经炎症。这项研究的目的是1。使用APP/PS1和TAU22小鼠对广告特征的饮酒过多2。描述NLRP3/ASC炎性小体成分在酒精介导的作用 AD小鼠中的神经炎症3。评估IL-1信号通路的贡献炎症体介导的神经炎症响应AD小鼠的饮酒。这些实验将提供有关酒精介导的炎性体作用的新见解在AD的开发和发展中激活并评估临床前干预措施通过靶向关键致病途径，中断炎症体介导的神经炎症在这项研究中发现。