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

描述(申请人提供)：微管相关蛋白tau(MAPT)的显著丝状包涵体和神经变性是许多神经退行性疾病的特征。虽然，许多这些肌萎缩侧索硬化症的确切病因仍不清楚，但在神经病理学上，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(IL-1)通过激活神经元IL1受体(IL1-R)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IL1-R/p38MAPK可能是治疗人类紧张症的一个独特的潜在药物靶点。大量研究表明，髓系分化主反应基因88(MyD88)是IL-1RS下游的关键适配子蛋白，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IL-1诱导的MAPT病理过程中的作用尚不清楚。鉴于脑免疫细胞内IL-1和IL-1-R在调节先天免疫和后天免疫中的重要性，本研究的目的是针对神经元-MyD88，研究其对全身炎症(脂多糖/脂多糖)和自发性疾病(HTau)小鼠模型中p38 MAPK激活、MAPT病理、神经炎症、神经变性和认知功能的影响。1)研究MyD88fl/fl/CaMKII-Cre转基因小鼠神经元限制性缺失对脂多糖诱导的MAPT病理、神经炎症、神经退行性变和行为功能的影响。2)将hTau、hTau-CX3CR1-/-小鼠与MyD88fl/fl/CaMKII-Cre转基因小鼠杂交，获得神经元MyD88缺失的hTau小鼠，研究不同月龄MAPT的病理、神经炎症、神经退行性变及行为功能。这些研究将使我们更好地了解肌萎缩侧索硬化症中神经元特异性的IL1-R/MyD88信号，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。

DESCRIPTION (provided by applicant): The 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 (IL-1) released by reactive microglia induces MAPT phosphorylation in primary neurons via activating neuronal IL1-receptor (IL1-R) and p38 mitogen activated protein kinase (p38 MAPK) pathway. Taken together, these results suggest that inhibition of neuronal IL1- R/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 IL-1Rs 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 IL-1 induced MAPT pathology is unclear. Given the importance of IL-1 and IL1-R within the immune cells of the brain in regulating innate and adoptive immunity, the goal of the current proposal is to specifically target neuronal-MyD88 and study its effect on p38 MAPK activation, MAPT pathology, neuroinflammation, neurodegeneration and cognitive function in mouse models of systemic inflammation (lipopolysaccharide/LPS) and tauopathy (hTau). This will be studied under two specific aims: 1) Study the effect of neuron-restricted deletion of MyD88 on LPS induced MAPT pathology, neuroinflammation, neurodegeneration and behavioral function in MyD88fl/fl/CamKII-Cre transgenic mice. 2) Generate hTau mice deficient for neuronal MyD88 via crossing hTau, hTau-Cx3cr1-/- mice to MyD88fl/fl/CamKII- Cre transgenic mice, and study MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. These studies will provide greater understanding of the neuron-specific IL1-R/MyD88 signaling in tauopathies and determine whether MyD88 can serve as a potential therapeutic target against inflammation-mediated MAPT pathology in human tauopathies.