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

小胶质细胞和神经元特异性 MyD88 信号传导在 tau蛋白病中的作用

• 批准号: 8546143
• 负责人: Kiran Bhaskar
• 金额: $ 19.27万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-16 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546143
• 关键词: ATF2 gene; Ablation; Age; Alzheimer' s Disease; Attenuated; Autopsy; Behavioral; Biochemical; Biochemistry; Brain; Brain Injuries; CX3CL1 gene; Cell Death; Cells; Down-Regulation; Drug Delivery Systems; Encephalitis; Etiology; FK506; Fractalkine; Functional disorder; Genes; Genetic; Goals; Human; Hypoxia; Immune; Immunity; Immunosuppressive Agents; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-1; Interleukin-1 Receptors; Ligands; Link; Lipopolysaccharides; MAP Kinase Gene; MAPT gene; Mediating; Microglia; Microtubules; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinase Kinases; Mus; MyD88 protein; Myelogenous; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome Study; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Process; Progressive Supranuclear Palsy; Prosencephalon; Protein Conformation; Receptor Signaling; Role; SB 203580; Signal Pathway; Signal Transduction; Silver; TLR4 gene; Tauopathies; Transgenic Mice; Transgenic Organisms; adapter protein; age related; behavioral impairment; brain cell; chemokine; cognitive function; corticobasal degeneration; cytokine; human CX3CR1 protein; human MAPK14 protein; human tissue; insight; mouse model; neuroinflammation; novel therapeutics; receptor; research study; response; tau Proteins; tau aggregation; tau phosphorylation; therapeutic target; toll-like receptor 4; transcription factor

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.

描述（由申请人提供）：微管相关蛋白tau（MAPT）和神经变性的显著丝状包涵体是许多神经变性tau蛋白病的标志。虽然，这些tau蛋白病中的许多的确切病因仍然难以捉摸，但在神经病理学上，它们的特征在于过度磷酸化的MAPT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tau蛋白病的病理生理学。然而，这些研究在很大程度上是相关的，并且没有提供神经炎症在神经退行性疾病过程中的作用的直接证据。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磷酸化，聚集和行为障碍的小鼠模型的tau蛋白病（hTau）。值得注意的是，当小鼠缺乏小胶质细胞特异性fractalkine受体CX 3CR 1时，小胶质细胞活化对MAPT病理学的影响增强。我们还证明，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（p38 MAPK）途径诱导原代神经元MAPT磷酸化。总之，这些结果表明，神经元IL 1- R/p38 MAPK的抑制可能代表了人类tau蛋白病的独特的潜在药物靶标。许多研究已经确定髓样分化初级应答基因88（MyD 88）是IL-1 R的关键下游衔接蛋白以及p38 MAPK活化的上游。最近的研究表明，MyD 88的遗传缺陷对缺氧诱导的脑损伤和全身性炎症小鼠模型具有保护作用。然而，MyD 88在介导IL-1诱导的MAPT病理中的作用尚不清楚。考虑到脑免疫细胞内IL-1和IL 1-R在调节先天性和过继性免疫中的重要性，当前提案的目标是特异性靶向神经元-MyD 88并研究其对全身性炎症（脂多糖/LPS）和tau蛋白病（hTau）小鼠模型中的p38 MAPK活化、MAPT病理学、神经炎症、神经变性和认知功能的影响。这将在两个具体目标下进行研究：1）研究MyD 88的神经元限制性缺失对MyD 88 fl/fl/CamKII-Cre转基因小鼠中LPS诱导的MAPT病理、神经炎症、神经变性和行为功能的影响。2)通过将hTau、hTau-Cx 3cr 1-/-小鼠与MyD 88 fl/fl/CamKII-Cre转基因小鼠杂交，产生神经元MyD 88缺陷的hTau小鼠，研究不同年龄段的MAPT病理、神经炎症、神经退行性变和行为功能。这些研究将提供对tau蛋白病中神经元特异性IL 1-R/MyD 88信号传导的更好理解，并确定MyD 88是否可以作为人类tau蛋白病中炎症介导的MAPT病理的潜在治疗靶点。