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: 10264088
• 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/10264088
• 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; Cleaved cell; 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; 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， 免疫信号通路，特别是NLRP 3炎性体激活发挥重要作用 无论是在AD还是酒精诱导的神经炎症中。然而，酒精的影响 在AD上的使用仍然很大程度上未知。我们研究的重点是评估 过度饮酒对AD的发展和进展的影响，并确定关键 可能提供治疗靶点的分子途径。多蛋白复合物的活化， PAMP或DAMP引起的炎性小体的活化涉及两种信号：首先，TLR介导的活化， 增加pro-IL-1 β和第二，NLRP介导的炎性小体组装和半胱天冬酶-1 活化，将IL-1 β原切割为成熟IL-1 β。我们之前发现IL-1 β NLRP 3/ASC炎性体的产生和半胱天冬酶-1在脑中的活化， 慢性酒精喂养。在AD的APP/PS1和Tau 22小鼠模型中，caspase-1活性和 IL-1 β的产生依赖于NLRP 3，NLRP 3炎性体激活驱动A β和tau 病理基于这些观察，我们假设长期酒精暴露 加速和加剧AD特征。我们假设慢性酒精诱导的 NLRP 3/ASC炎性小体激活通过以下途径促进AD的发生和进展： 放大的神经炎症本研究的目的是1。为了描述长期 以及过量饮酒对APP/PS1和Tau 22小鼠AD特征的影响2.到 描述NLRP 3/ASC炎性体组分在酒精介导的 AD小鼠的神经炎症3.目的探讨IL-1信号通路在肿瘤细胞凋亡中的作用。 炎症小体介导的神经炎症对AD小鼠饮酒的反应。 这些实验将为酒精介导的炎性小体的作用提供新的见解。 激活AD的发展和进展，并评估临床前干预措施， 通过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。