The role of inflammasome signaling in tauopathies

炎症小体信号传导在 tau蛋白病中的作用

基本信息

批准号：
9230877
负责人：
Kiran Bhaskar
金额：
$ 33.14万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9230877
关键词：
Adaptor Signaling Protein Adoptive Transfer Affect Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Apoptosis Automobile Driving Axonal Transport Brain CCL2 gene Caspase Cell Culture System Cells Cellular Stress Chronic Cleaved cell Complex Defect Disease Doxycycline Drug Targeting Encephalitis Etiology Extracellular Space Functional disorder Genes Genetic Goals Human Image Immune Immune system Impaired cognition Impairment In Vitro Individual Infiltration Inflammasome Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 Interleukin-1 Receptors Intervention Knock-out Lead Learning Lesion Leukocytes MAPK14 gene MAPT gene Mediating Messenger RNA Microglia Microtubules Modeling Modification Morphology Multiprotein Complexes Mus Mutation Nerve Degeneration Neuraxis Neurofibrillary Tangles Neurons Nitric Oxide Synthase Non-Steroidal Anti-Inflammatory Agents Outcome Study Pathologic Pathology Pathway interactions Peripheral Pharmaceutical Preparations Process Protein Conformation Proteins Rattus Recruitment Activity Role Short-Term Memory Signal Pathway Signal Transduction Synapses Tauopathies Testing Therapeutic Time Transgenic Mice Transgenic Organisms United States Up-Regulation age related base behavioral impairment brain parenchyma cognitive function exosome extracellular feeding fractalkine receptor genetic association hTau Mice humanized mouse in vivo injured insight loss of function mutation macrophage misfolded protein mitogen-activated protein kinase p38 monocyte mouse model neuroinflammation new therapeutic target novel outcome forecast overexpression prevent public health relevance research study sensor tau Proteins tau aggregation tau expression tau phosphorylation therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Tangle pathology is one of the major pathological hallmarks of Alzheimer's disease (AD) and related tauopathies, where microtubule associated protein - tau (or tau) acquires a pathological protein conformation, accumulates as neurofibrillary tangles (NFTs) and coincides with neurodegeneration. Increasing evidence suggests that age-related alterations in inflammatory processes also closely associated with NFT pathology in the brains of individuals with human and mouse models of tauopathies. While it is hypothesized that accumulation misfolded proteins released from injured neurons and synapses may trigger neuroinflammation, it is not clear how misfolding of proteins intrinsic to neurons, such NFTs, trigger neuroinflammation. Previous studies have documented that neurodegenerative lesions caused by truncation of human tau promoted inflammatory response including upregulation of numerous immune molecules and morphological activation of microglial cells in a rat model of tauopathy. Furthermore, NFT lesions in this model also promoted infiltration and recruitment of peripheral leukocytes into the brain parenchyma. In another study, microglial activation preceded NFT pathology in P301S mouse model of tauopathy. We have recently demonstrated a progressive and age-dependent neuroinflammation in hTau mouse model of tauopathy. First, robust microglial activation was observed in 12 month and 18 month old hTau mice compared to 18 month old non-transgenic controls. Second, a significant increase in mRNA levels for inflammatory molecules such as nitric-oxide synthase-2 (NOS2) and monocyte chomoattractant protein (MCP1 or CCL2) was observed in the brains of much younger, 6 month old hTau mice. Finally, enhancing microglia-specific neuroinflammation accelerated tau phsphorylation, aggregation and behavioral impairment in hTau mouse model of tauopathy. Notably, the interleukin-1 (IL-1) released by reactive microglia induces tau phosphorylation via activating neuronal IL-1 receptor (IL-1R) and p38 mitogen activated protein kinase pathway. While these studies suggested that microglial activation and IL-1 signaling is involved in accelerating tau pathology and neurodegeneration, the factor(s) driving microglial activation and/or secretion of IL-1 is unclear. In our preliminary studies, we have observed that misfolded tau could act as 'danger signal' to stimulate secretion of IL-1� via assembly of a multiprotein complex called "inflammasome", which includes ASC as a key component of inflammasome complex. Based on this novel phenomenon from our preliminary studies, we propose to determine whether misfolded tau trigger inflammasome assembly/maturation of IL-1� and lead to microglial activation in vitro (Specific Aims 1) and in rTg4510 regulatable mouse model of tauopathy (Specific Aim 2). We also propose to determine whether blocking inflammasome assembly via genetic deficiency of ASC prevents IL-1� activation, microglial neuroinflammation and block tau pathology in hTau mice crossed to ASC-/- and ASCfl/fl mice (Specific Aim 3). The outcome of these studies will provide greater understanding of the tau pathology and innate immune responses mediated by inflammasome/IL-1� and present opportunities in identifying novel therapeutic targets against tauopathies.

描述（由申请人提供）：缠结病理学是阿尔茨海默氏病 (AD) 和相关 tau 病的主要病理特征之一，其中微管相关蛋白 - tau（或 tau）获得病理性蛋白质构象，累积为神经原纤维越来越多的证据表明，与年龄相关的炎症过程的改变也与人类和小鼠 tau蛋白病模型的大脑中的 NFT 病理密切相关，但受损释放的错误折叠蛋白却不会累积。神经元和突触可能会引发神经炎症，但目前尚不清楚神经元固有的蛋白质（例如 NFT）的错误折叠如何引发神经炎症。在tau蛋白病大鼠模型中，人类tau蛋白截短引起的神经退行性病变促进了炎症反应，包括大量免疫分子的上调和小胶质细胞的形态激活。此外，该模型中的NFT损伤还促进了外周白细胞向脑实质的浸润和募集。在另一项研究中，在 P301S tau 蛋白病小鼠模型中，小胶质细胞激活先于 NFT 病理，我们最近证明了一种进行性且与年龄相关的神经炎症。首先，与 18 个月大的非转基因对照组相比，在 12 个月和 18 个月大的 hTau 小鼠中观察到强烈的小胶质细胞激活；其次，一氧化氮合酶等炎症分子的 mRNA 水平显着增加。 -2 (NOS2) 和单核细胞趋色蛋白 (MCP1 或 CCL2) 在更年轻的 6 个月大 hTau 小鼠的大脑中观察到。增强小胶质细胞特异性神经炎症加速 hTau 蛋白病小鼠模型中的 tau 蛋白磷酸化、聚集和行为障碍值得注意的是，反应性小胶质细胞释放的白介素-1 (IL-1) 通过激活神经元 IL-1 受体 (IL-1R) 诱导 tau 蛋白磷酸化。和 p38 丝裂原激活蛋白激酶途径，而这些研究表明小胶质细胞激活和 IL-1 信号传导参与加速。在 tau 病理学和神经退行性疾病中，驱动小胶质细胞激活和/或分泌 IL-1 的因素尚不清楚。在我们的初步研究中，我们观察到错误折叠的 tau 可能充当刺激 IL-1 分泌的“危险信号”。通过组装称为“炎症小体”的多蛋白复合物，其中 ASC 作为炎症小体复合物的关键成分。基于我们初步研究中的这一新现象，我们建议确定是否会触发错误折叠的 tau 蛋白。 IL-1� 炎症小体组装/成熟并导致体外小胶质细胞激活（具体目标 1）和 rTg4510 可调节 tau 蛋白病小鼠模型（具体目标 2）我们还建议确定是否通过 ASC 遗传缺陷阻断炎症小体组装。 hTau 小鼠与 ASC-/- 和 ASCfl/fl 交叉的 IL-1� 激活、小胶质细胞神经炎症和阻断 tau 病理学这些研究的结果将加深对炎症小体/IL-1介导的 tau 病理学和先天免疫反应的了解，并为识别针对 tau 病的新治疗靶点提供机会。