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: 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
• 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' 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; 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

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 以及与酒精相关的脑损伤。之前的研究，包括我们自己的研究，都表明先天的 免疫信号通路尤其是 NLRP3 炎症小体激活发挥重要作用 AD 和酒精引起的神经炎症。然而，重度酒精的影响 AD 的使用仍然很大程度上未知。我们研究的重点是评估效果 过量饮酒对 AD 发生和进展的影响并确定关键 可能提供治疗靶点的分子途径。多蛋白复合物的激活， 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。我们之前显示 IL-1ß 增加 NLRP3/ASC 炎性体和 caspase-1 在大脑中激活后产生 长期酗酒。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 病理。根据这些观察，我们假设长期饮酒 加速并加剧AD特征。我们假设慢性酒精诱发 NLRP3/ASC 炎症小体激活通过以下途径促进 AD 的发生和进展 神经炎症放大。本研究的目的是 1. 描述长期影响 使用 APP/PS1 和 Tau22 小鼠 2. 观察过度饮酒对 AD 特征的影响 描述 NLRP3/ASC 炎症小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小体的作用提供新的见解 AD 发生和进展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。