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: 8462009
• 负责人: Kiran Bhaskar
• 金额: $ 18.21万
• 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/8462009
• 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 Targeting; 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）的突出丝状包涵体和神经变性是许多神经退行性tau病的标志。虽然，许多这些牛头病变的确切病因尚不清楚，但在神经病理学上，它们的特征是细胞内过度磷酸化的MAPT聚集、神经炎症和细胞死亡。越来越多的证据表明，神经炎症可能直接促进神经退行性病变的病理生理。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病（hTau）。值得注意的是，当小鼠缺乏小胶质特异性fractalkine受体CX3CR1时，小胶质细胞激活对MAPT病理的影响增强。我们还证明了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 -r）和p38丝裂原活化蛋白激酶（p38 MAPK）途径诱导初级神经元MAPT磷酸化。综上所述，这些结果表明抑制神经元il - 1- R/p38 MAPK可能是治疗人类牛头病变的一个独特的潜在药物靶点。大量研究已经证实髓系分化初级反应基因88 （MyD88）是IL-1Rs的下游关键适配蛋白，也是p38 MAPK激活的上游关键适配蛋白。最近的研究表明，MyD88基因缺乏对缺氧引起的脑损伤和全身性炎症小鼠模型具有保护作用。然而，MyD88在介导IL-1诱导的MAPT病理中的作用尚不清楚。鉴于脑免疫细胞内IL-1和il - r在调节先天和过性免疫中的重要性，本研究的目标是特异性靶向neuronal-MyD88，研究其在全身性炎症（脂多糖/LPS）和tau病（hTau）小鼠模型中对p38 MAPK激活、MAPT病理、神经炎症、神经变性和认知功能的影响。我们将从两个方面进行研究：1)研究神经元限制性缺失MyD88对LPS诱导的MyD88fl/fl/CamKII-Cre转基因小鼠的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- cx3cr1 -/-小鼠与MyD88fl/fl/CamKII- Cre转基因小鼠杂交，生成神经元MyD88缺失的hTau小鼠，研究不同年龄的MAPT病理、神经炎症、神经变性和行为功能。这些研究将进一步了解牛头病变中神经元特异性il - 1- r /MyD88信号，并确定MyD88是否可以作为对抗人类牛头病变中炎症介导的MAPT病理的潜在治疗靶点。