The role of microglial- and neuron-specific MyD88 signaling in tauopathies

描述(申请人提供)：显著的微管相关蛋白tau丝状包涵体(MAPT)和神经变性是许多神经退行性疾病的特征。尽管许多tauopy病的确切病因仍不清楚，但从神经病理学角度来看，它们的特征是MAPT过度磷酸化的细胞内聚集、神经炎症和细胞死亡。越来越多的证据表明，神经炎症可能直接导致神经退行性病变的病理生理学。然而，这些研究在很大程度上是相关的，并没有提供神经炎症在神经退行性疾病过程中所起作用的直接证据。我们最近提供了令人信服的证据表明，神经炎症，细胞自主的小胶质细胞，加速MAPT的磷酸化，聚集和行为障碍在牛磺酸(HTau)小鼠模型中。值得注意的是，当小鼠缺乏小胶质细胞特异性的Fractalkine受体CX3CR1时，小胶质细胞激活对MAPT病理的影响增强。我们还证实，反应性小胶质细胞释放的白介素1(IL1)通过激活神经元IL1受体(IL1R)和p38丝裂原活化蛋白激酶(P38MAPK)途径，诱导原代神经元MAPT磷酸化。综上所述，这些结果表明，抑制神经元IL1R/p38MAPK可能是治疗人类肌萎缩侧索硬化症的独特潜在药物靶点。大量研究表明，髓系分化主反应基因88(MyD88)是IL1Rs下游的关键适配蛋白，也是p38 MAPK激活的上游接头蛋白。最近的研究表明，MyD88的遗传缺陷对缺氧性脑损伤和小鼠全身炎症模型具有保护作用。然而，MyD88在介导IL1诱导的MAPT病理过程中的作用尚不清楚。同样不清楚的是，小胶质细胞来源的IL1是否反馈到小胶质细胞本身，诱导自我传播的IL1信号，从而促进神经元MAPT病理和神经退变。基于我们最近的一项研究，即小胶质细胞特异性神经炎症足以通过IL1-p38MAPK途径诱导神经元MAPT病理和认知功能障碍，本研究的目标是通过靶向、细胞特异性缺失MyD88来特异性靶向小胶质细胞特异性和神经元特异性IL1R信号，并在两种特定目的下研究其对p38MAPK激活、MAPT病理、神经炎症、神经变性和认知功能的影响。1)研究hTau小鼠前脑神经元限制性缺失MyD88基因对不同月龄MAPT病理、神经炎症、神经退行性变和行为功能的影响。2)研究hTau小鼠MyD88小胶质细胞限制性缺失对不同月龄MAPT病理、神经炎症、神经退行性变和行为功能的影响。这些研究将使我们更好地了解IL1R/MyD88信号在肌萎缩侧索硬化症中的细胞自主作用，并确定MyD88是否可以作为治疗人类肌萎缩侧索硬化症炎症介导的MAPT病理的潜在靶点。 公共卫生相关性：越来越多的证据表明，与年龄相关的脑炎症可能在tau介导的神经退行性变中发挥重要作用，在许多人类tau病中。我们小组最近的一项研究提供了令人信服的证据，表明小胶质细胞特异性神经炎症加速了tau病理和人源化tau病小鼠模型(HTau)的认知障碍。值得注意的是，从激活的小胶质细胞释放的白细胞介素1(IL1)通过IL1受体(IL1R)信号通路上调神经元p38丝裂原活化蛋白激酶(P38MAPK)和tau过度磷酸化。在本研究中，通过缺失IL1R采用蛋白MyD88，前脑神经元和小胶质细胞特异性地阻断IL1R信号，对tau病理、神经退行性变和行为功能的影响将在hTau小鼠人类变态反应模型中进行研究。这项研究的结果将探索神经元特异性和前馈小胶质细胞IL1信号在肌萎缩侧索硬化症中的作用，并提供在多细胞水平上对IL1R/MyD88信号的机制见解，作为对抗人类肌萎缩侧索硬化症的治疗靶点。

DESCRIPTION (provided by applicant): Prominent filamentous inclusions of microtubule-associated protein tau (MAPT) and neurodegeneration are hallmarks of many neurodegenerative tauopathies. Although the exact etiology of many of these tauopathies remains elusive, neuropathologically they are characterized by intracellular aggregates of hyperphosphorylated MAPT, neuroinflammation and cell death. Increasing evidence suggests that neuroinflammation may directly contribute to the pathophysiology of neurodegenerative tauopathies. However, these studies are largely correlative, and do not provide direct evidence of the role of neuroinflammation in the neurodegenerative disease process. We have recently provided compelling evidence that neuroinflammation, cell-autonomous to microglia, accelerates MAPT phosphorylation, aggregation and behavioral impairment in a mouse model of tauopathy (hTau). Notably, the effects of microglial activation on MAPT pathology were enhanced when mice were deficient for the microglial-specific fractalkine receptor, CX3CR1. We also demonstrated that interleukin-1 (IL1) released by reactive microglia induces MAPT phosphorylation in primary neurons via activating neuronal IL1 receptor (IL1R) and p38 mitogen activated protein kinase (p38 MAPK) pathway. Taken together, these results suggest that inhibition of neuronal IL1R/p38 MAPK may represent a unique potential drug target for human tauopathies. Numerous studies have established that Myeloid Differentiation primary response gene 88 (MyD88) is a key downstream adapter protein for IL1Rs as well as upstream for p38 MAPK activation. Recent studies have suggested that genetic deficiency of MyD88 is protective against hypoxia induced brain injury and mouse model of systemic inflammation. However, the role of MyD88 in mediating IL1 induced MAPT pathology is unclear. Also not clear is whether or not microglial-derived IL1 feeds-back to microglia themselves to induce self-propagating IL1 signaling that contributes to neuronal MAPT pathology and neurodegeneration. Based on our recent study that microglia-specific neuroinflammation is sufficient to induce neuronal MAPT pathology and cognitive impairment via IL1-p38MAPK pathway, the goal of the current proposal is to specifically target microglia-specific and neuronal-specific IL1R signaling via targeted, cel-specific deletion of MyD88 and study its effect on p38 MAPK activation, MAPT pathology, neuroinflammation, neurodegeneration and cognitive function in a mouse model of tauopathy (hTau) under two specific aims. 1) Study the effect of forebrain neuron- restricted deletion of MyD88 in hTau mice on MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. 2) Study the effect of microglia-restricted deletion of MyD88 in hTau mice on MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. These studies will provide greater understanding of cell autonomous contribution of IL1R/MyD88 signaling in tauopathies and determine whether MyD88 can serve as a potential therapeutic target against inflammation- mediated MAPT pathology in human tauopathies. PUBLIC HEALTH RELEVANCE: Accumulating evidence suggests that the age-related brain inflammation may play an important role in tau-mediated neurodegeneration in numerous human tauopathies. A recent study from our group has provided compelling evidence that microglia-specific neuroinflammation accelerates tau pathology and cognitive impairment in humanized mouse model of tauopathy (hTau). Notably, interneukin-1 (IL1) released from activated microglia is responsible for upregulating neuronal p38 mitogen activated protein kinase (p38 MAPK) and tau hyperphosphorylation via IL1 receptor (IL1R) signaling pathway. In the current study, the effect of forebrain neuron- and microglia-specific ablation of IL1R signaling via deletion of an IL1R adopter protein, MyD88, on tau pathology, neurodegeneration and behavioral function will be studied in the hTau mouse model of human tauopathy. The outcome of this study will explore the role of neuron-specific as well as feed-forward microglial IL1 signaling in tauopathies and provide mechanistic insights on IL1R/MyD88 signaling at multiple cellular levels as a therapeutic target against human tauopathies.