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：
10471334
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/10471334
关键词：
APP-PS1 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 Interleukin-1 beta 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 Pharmacology Play Production Proteins Reporting Research Role Signal Pathway Signal Transduction Testing Vertebral column Water alcohol effect alcohol exposure alcohol response anakinra antagonist base brain tissue chronic alcohol ingestion cytokine drinking water epidemiologic data experimental study feeding insight mouse model neuroinflammation novel 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病 (AD) 发病机制的一个关键特征先前的研究，包括我们自己的研究，都表明先天性的。免疫信号通路尤其是 NLRP3 炎症小体激活发挥重要作用然而，在 AD 和酒精引起的神经炎症中，重度酒精的影响却更大。我们研究的重点是评估 AD 的效果。过量饮酒对 AD 发生和进展的影响并确定关键可能提供多蛋白复合物激活的分子途径， PAMP 或 DAMP 的炎症小体涉及两个信号：第一，TLR 介导的激活增加 pro-IL-1ß 和其次，NLRP 介导的炎症小体组装和 caspase-1 激活将原 IL-1ß 裂解为成熟的 IL-1ß 我们之前表明 IL-1ß 增加。 NLRP3/ASC 炎性体和 caspase-1 在大脑中激活后产生在 AD 的 APP/PS1 和 Tau22 小鼠模型中，Caspase-1 活性和 IL-1ß 的产生依赖于 NLRP3 和 NLRP3 炎性体激活驱动 Aß 和 tau 根据这些观察，我们发现了慢性酒精暴露。我们假设慢性酒精会加速和恶化 AD 特征。 NLRP3/ASC 炎症小体激活通过以下途径促进 AD 的发生和进展本研究的目的是 1. 表征长期影响。使用 APP/PS1 和 Tau22 小鼠 2. 观察过量饮酒对 AD 特征的影响描述 NLRP3/ASC 炎性体成分在酒精介导中的作用 3.评估IL-1信号通路在AD小鼠神经炎症中的作用 AD 小鼠饮酒后炎症体介导的神经炎症。这些实验将为酒精介导的炎症的作用提供新的见解 AD 发生和进展过程中的激活并评估临床前干预措施通过靶向关键致病途径来中断炎症小体介导的神经炎症在这项研究中发现。