The role of inflammasome signaling in tauopathies

描述(申请人提供)：缠绕病理是阿尔茨海默病(AD)和相关tauopathy的主要病理特征之一，微管相关蛋白tau(或tau)获得一种病理蛋白构象，以神经原纤维的形式积聚。 缠绕(NFT)，并与神经退行性变重合。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tauopathy模型患者大脑中的NFT病理密切相关。虽然假设从受损的神经元和突触释放的错误折叠的蛋白质可能会引发神经炎症，但尚不清楚神经元固有的蛋白质错误折叠是如何引发神经炎症的。先前的研究已经证明，在tau病大鼠模型中，截短tau引起的神经退行性损伤促进了炎症反应，包括许多免疫分子的上调和小胶质细胞的形态激活。此外，该模型中的NFT损伤也促进了外周血白细胞向脑实质的渗透和募集。在另一项研究中，小胶质细胞的激活先于NFT病理，在P301S小鼠的尾部病变模型中。我们最近在hTau小鼠的脊椎病模型中证明了一种进行性的和年龄相关的神经炎症。首先，12个月和18个月大的hTau小鼠与18个月大的非转基因对照组相比，观察到了强劲的小胶质细胞激活。其次，在更年轻的6个月大的hTau小鼠的大脑中，观察到一氧化氮合酶2(NOS2)和单核细胞趋化蛋白(MCP1或CCL2)等炎症分子的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蛋白的磷酸化、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)通过激活神经元白介素1受体(IL-1R)和p38丝裂原激活的蛋白激酶途径诱导tau的磷酸化。虽然这些研究表明小胶质细胞激活和IL-1信号转导参与加速tau病理和神经退变，但驱动小胶质细胞激活和/或分泌IL-1的因素(S)尚不清楚。在我们的初步研究中，我们观察到错误折叠的tau可以作为刺激IL-1？的分泌的“危险信号”，通过组装一个称为“炎症体”的多蛋白复合体，其中包括ASC作为炎症体复合体的关键成分。基于我们初步研究中的这一新现象，我们建议确定错误折叠的tau是否会在体外(特异性目标1)和rTg4510可调节的tau病小鼠模型(特异性目标2)中触发IL-1的炎症体组装/成熟并导致小胶质细胞激活。我们还建议确定通过ASC遗传缺陷来阻止炎症体组装是否可以阻止hTau小鼠与ASC-/-和ASCf1/fl小鼠杂交(特异性目标3)的IL-1ç激活、小胶质细胞神经炎和阻断tau病理。这些研究的结果将提供对tau病理和由炎症小体/IL-1？介导的先天免疫反应的更多了解，并为寻找针对tau病的新的治疗靶点提供机会。

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-1ß 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-1ß 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-1ß 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-1ß and present opportunities in identifying novel therapeutic targets against tauopathies.