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：
8804963
负责人：
Kiran Bhaskar
金额：
$ 33.03万
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 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8804963
关键词：
Adoptive Transfer Affect Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Apoptosis Automobile Driving Axonal Transport Brain CCL2 gene CX3CL1 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 Genetic screening method Goals Health Human Image Immune Immune response Immune system Impaired cognition In Vitro Individual Infiltration Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 Receptors Intervention Knock-out Lead Learning Lesion Leukocytes Mediating Messenger RNA Microglia Microtubules Modeling Modification Multiprotein Complexes Mus Mutation Nerve Degeneration Neuraxis Neurofibrillary Tangles Neurons Nitric Oxide Synthase Non-Steroidal Anti-Inflammatory Agents Outcome Study Pathology Pathway interactions Peripheral Pharmaceutical Preparations Process Protein Conformation Proteins Rattus Receptor Signaling Role Short-Term Memory Signal Pathway Signal Transduction Staging Synapses Tauopathies Testing Therapeutic Time Transgenic Mice Transgenic Organisms United States Up-Regulation adapter protein age related base behavioral impairment cognitive function extracellular feeding fractalkine receptor genetic association hTau Mice human MAPK14 protein in vivo injured insight loss of function mutation macrophage monocyte mouse model neuroinflammation new therapeutic target novel outcome forecast overexpression prevent protein misfolding 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（由适用提供）：缠结病理学是阿尔茨海默氏病（AD）和相关的陶氏病的主要病理标志之一，其中微管相关蛋白质-tau（或tau）获得了病理蛋白质构象，它作为神经纤维纤维质构型积累缠结（NFT），与神经变性一致。越来越多的证据表明，炎症过程中与年龄相关的变化也与人类和小鼠模型的人的大脑中的NFT病理学密切相关。虽然假设从受伤的神经元和突触释放出的积累不折叠的蛋白质可能会触发神经炎症，但尚不清楚对神经元（此类NFT，触发神经毒素）固有的蛋白质固有的错误折叠是如何错误折叠的。先前的研究表明，由人tau截断引起的神经退行性病变促进了炎症反应，包括上调许多免疫分子和小鼠青霉病模型中小胶质细胞的形态激活。此外，该模型中的NFT病变还促进了外周白细胞浸润和募集到脑实质中。在另一项研究中，小胶质细胞激活先前是auopathy小鼠模型的NFT病理学。最近，我们证明了在tauopathy的HTAU小鼠模型中逐渐依赖于年龄的神经炎症。首先，与18个月大的非转基因对照相比，在12个月零18个月大的HTAU小鼠中观察到了强大的小胶质细胞激活。其次，在年轻的6个月大的HTAU小鼠的大脑中观察到了炎性分子（例如硝酸氧化物合酶2（NOS2）和单核细胞chomoattactals蛋白（MCP1或CCL2）的mRNA水平显着升高。最后，在tauopathy的HTAU小鼠模型中，增强了小胶质细胞特异性神经炎症加速，聚集和行为障碍。值得注意的是，由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）和p38有丝分裂激活的蛋白激酶途径诱导tau磷酸化。尽管这些研究表明小胶质细胞激活和IL-1信号传导参与加速tau病理学和神经变性，但驱动小胶质细胞激活和/或分泌IL-1的因子尚不清楚。在我们的初步研究中，我们观察到，错误折叠的tau可以通过组装称为“炎症体”的多蛋白复合物的组装来刺激IL-1的分泌“危险信号”，其中包括ASC作为炎症体复合物的关键成分。基于我们的初步研究的这种新现象，我们建议确定错误折叠的tau触发炎症体组装/IL-1的成熟，并在体外导致小胶质细胞激活（特定目的1）和RTG4510中调节的小鼠模型的tauopathy模型（特定目标2）。我们还建议确定通过ASC遗传缺乏阻断炎性体组装是否可以防止IL-1？激活，小胶质细胞神经炎症和阻断越过ASC的HTAU小鼠的TAU病理学的障碍物 - / - 和ASCFL/FL小鼠（特定的AIM 3）。这些研究的结果将提供对炎症体/IL-1介导的TAU病理学和先天免疫反应的更深入的了解，并在确定针对Tauopathies的新型治疗靶标方面提供了机会。