The role of inflammasome signaling in tauopathies

描述（由申请人提供）：缠结病理学是阿尔茨海默病（AD）和相关tau蛋白病的主要病理学标志之一，其中微管相关蛋白- tau（或tau）获得病理性蛋白质构象，作为神经递质累积 缠结（NFT），并与神经退行性变一致。越来越多的证据表明，炎症过程中与年龄相关的改变也与患有tau蛋白病的人和小鼠模型的个体的大脑中的NFT病理密切相关。虽然假设从损伤的神经元和突触释放的错误折叠的蛋白质的积累可能触发神经炎症，但尚不清楚神经元固有的蛋白质（例如NFT）的错误折叠如何触发神经炎症。先前的研究已经证明，在大鼠tau蛋白病模型中，由人tau蛋白截短引起的神经退行性病变促进了炎症反应，包括许多免疫分子的上调和小胶质细胞的形态学活化。此外，该模型中的NFT病变还促进了外周白细胞向脑实质中的浸润和募集。在另一项研究中，在tau蛋白病的P301 S小鼠模型中，小胶质细胞活化先于NFT病理。我们最近在tau蛋白病的hTau小鼠模型中证明了进行性和年龄依赖性神经炎症。首先，与18月龄非转基因对照相比，在12月龄和18月龄hTau小鼠中观察到稳健的小胶质细胞活化。第二，在更年轻的6个月大的hTau小鼠的大脑中观察到炎症分子如一氧化氮合酶-2（NOS 2）和单核细胞趋化蛋白（MCP 1或CCL 2）的mRNA水平显著增加。最后，增强小胶质细胞特异性神经炎症加速了tau蛋白病的hTau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，由反应性小胶质细胞释放的白细胞介素-1（IL-1）通过激活神经元IL-1受体（IL-1 R）和p38丝裂原活化蛋白激酶途径诱导tau蛋白磷酸化。虽然这些研究表明小胶质细胞活化和IL-1信号传导参与加速tau病理学和神经变性，但驱动小胶质细胞活化和/或IL-1分泌的因素尚不清楚。在我们的初步研究中，我们已经观察到错误折叠的tau可以作为“危险信号”，通过组装称为“炎性体”的多蛋白复合物刺激IL-1的分泌，其中包括ASC作为炎性体复合物的关键组分。基于我们初步研究的这种新现象，我们提出确定错误折叠的tau是否触发IL-1的炎性体组装/成熟并导致体外小胶质细胞活化（特异性目的1）和rTg 4510可调控的tau蛋白病小鼠模型（特异性目的2）。我们还提出确定通过ASC的遗传缺陷阻断炎性小体组装是否防止了与ASC-/-和ASCfl/fl小鼠杂交的hTau小鼠中的IL-1？活化、小胶质细胞神经炎症和阻断tau病理（特异性目的3）。这些研究的结果将提供对tau病理学和由炎性小体/IL-1介导的先天免疫应答的更好理解，并为识别针对tau蛋白病的新治疗靶点提供机会。

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.