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

• 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
• 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' s Disease; Alzheimer' 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

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)发病机制的一个重要特征 和酒精相关的脑损伤。以前的研究，包括我们自己的研究，已经表明先天的 免疫信号通路尤其是NLRP3炎性小体的激活起着重要作用 在阿尔茨海默病和酒精诱导的神经炎症中都是如此。然而，重酒的影响 在AD上的使用在很大程度上仍不清楚。我们研究的重点是评估 过量饮酒对阿尔茨海默病的发生和发展的影响 可能提供治疗靶点的分子途径。激活多蛋白复合体， 由PAMPS或DAMPS引起的炎症体涉及两个信号：第一，TLR介导的激活 增加前IL-1和第二，NLRP介导的炎症体组装和caspase-1 将原IL-1？裂解为成熟IL-1？的激活。我们之前显示IL-1？升高 脑内NLRP3/ASC炎症体和caspase-1活化的产物 长期饮酒。在AD的APP/PS1和Tau22小鼠模型中，caspase-1活性和 IL-1的产生依赖于NLRP3和NLRP3炎性小体的激活驱动A？和tau 病理学。基于这些观察，我们假设慢性酒精暴露 加速和加剧AD功能。我们假设慢性酒精引起的 NLRP3/ASC炎性小体激活参与AD的发生发展 放大的神经炎症。本研究的目的是：1.表征长期治疗的效果 并使用APP/PS1和Tau22小鼠2对AD功能进行过量饮酒。 NLRP3/ASC炎性小体成分在酒精介导中的作用 阿尔茨海默病小鼠的神经炎症反应3.探讨IL-1信号通路在AD发病机制中的作用 阿尔茨海默病小鼠饮酒后炎症小体介导的神经炎症反应。 这些实验将为酒精介导的炎症小体的作用提供新的见解 阿尔茨海默病发生和发展过程中的激活并评估临床前干预措施 靶向关键致病途径阻断炎性小体介导的神经炎症 在这项研究中发现。