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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）：缠结病理是阿尔茨海默病（AD）和相关tau病的主要病理标志之一，其中微管相关蛋白- tau（或tau）获得病理蛋白构象，作为神经原纤维积累