The Role of Inflammasome Signaling in Tauopathies

炎症小体信号传导在 Tau蛋白病中的作用

基本信息

批准号：
9887762
负责人：
Kiran Bhaskar
金额：
$ 274.58万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9887762
关键词：
Adaptor Signaling Protein Address Affect Age-Months Antigen-Antibody Complex Apoptosis Autopsy Axon Behavioral Biochemical Biological Markers Bioluminescence Brain Brain region Cell Surface Receptors Cerebrospinal Fluid Chronic Data Development Diagnosis Encephalitis Extracellular Space Flow Cytometry Goals Human Immune signaling Immunotherapy Impaired cognition Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 beta Intervention Knockout Mice Lead Link Luciferases Magnetic Resonance Imaging Measurement Memory Microglia Modeling Modification Molecular Mus Myelogenous Nerve Degeneration Neurofibrillary Tangles Neurons Neutralization Tests Nuclear Outcome Study Pathologic Pathology Pathway interactions Process Proteins Reporter Role Route Sampling Signal Pathway Signal Transduction Small Interfering RNA Structure Synapses Tauopathies Testing Therapeutic Time Toll-like receptors Vaccines Virus-like particle base cognitive function effective therapy efficacy testing experimental study extracellular gain of function gray matter hTau Mice hyperphosphorylated tau immune activation improved in vivo inhibitor/antagonist monomer mouse model neuroinflammation neutralizing antibody novel novel therapeutic intervention prevent prophylactic receptor recruit response targeted treatment tau Proteins tau dysfunction white matter

项目摘要

PROJECT SUMMARY The primary goal of this project is to determine whether pathological forms of tau (pTau) – a significant pathological hallmark of neurodegenerative tauopathies, can activate interleukin-1β (IL-1β) through MyD88- dependent nuclear factor-kB (NF-kB) and NLRP3-ASC inflammasome pathway to cause neuroinflammation, axonal and white matter pathology, synaptic loss and cognitive impairment. The goal is also to test the efficacy of a novel pTau-targeted virus-like particle (VLP)-based immunotherapy strategy against pTau-induced neuroinflammation in hTau model of tauopathy. Recent studies have suggested that once tau is hyperphosphorylated and misfolded, the neurons tend to expel pTau to the extracellular space, which is taken up by other neurons and results in trans-neuronal propagation of pTau. We made a compelling discovery that en route to other neurons, pTau can also interact with and serve as an initial trigger to lead to microglial activation and neuroinflammation. However, it is not clear how exactly pTau can induce innate immune activation within microglia. Our preliminary results suggest the possibility that neuronally-derived pTau upregulates microglial cell surface receptors like toll-like receptors (TLRs), engage MyD88 (a key adapter protein common for various TLRs and IL-1Rs), activate NF-kB and NLRP3-ASC inflammasomes and lead to maturation of IL-1β in microglia. Strikingly, suppression of pTau in vivo, microglial-specific deletion of MyD88 or ASC, significantly reduced IL-1β maturation. Intriguingly, clearing pTau via VLP-based vaccine reduces MyD88 expression, neuroinflammation, tau pathology and improves memory. Based on these preliminary observations we hypothesize that pTau activates NF-kB-NLRP3-ASC inflammasomes-IL-1β innate immune complex through TLR/MyD88-dependent pathway in microglia. Targeting pTau (by VLP-based immunotherapy), MyD88 or IL-1R1 accessory protein (IL- 1RAcP) at different levels of this cascade blocks the feed-forward induction of brain inflammation induced by tau. We will test this hypothesis under three Specific Aims. In the Specific Aim 1, we propose to determine if different forms of pTau from post-mortem human brains trigger NF-kB priming by MyD88 and IL-1β maturation by NLRP3-ASC-inflammasomes pathways. In Specific Aim 2, we propose to determine if pTau-induced progressive NF-kB activation, neuroinflammation, MRI-based structural alterations and cognitive dysfunction is MyD88/IL-1RAcP dependent in hTau mouse model of tauopathy. Finally, in Specific Aim 3, we will determine if blocking pTau by VLP-based immunotherapy reduces NF-kB priming and IL-1β maturation as well as restore memory in hTau mice. This successful outcome of this study will determine whether pTau triggers neuroinflammation via MyD88-NF-kB-NLRP3-ASC inflammasomes-IL-1β pathway. This will of high significance for the development and testing of the VLP-based pTau-targeted therapeutics against neuroinflammation in tauopathies.

项目摘要该项目的主要目标是确定tau（PTAU）的病理形式是否是重要的神经退行性tauopathies的病理标志可以通过MyD88-激活白介素1β（IL-1β）依赖性的核因子-KB（NF-KB）和NLRP3-爆发途径引起神经炎症，轴突和白质病理学，突触损失和认知障碍。目标也是测试效率针对PTAU诱导的新型PTAU靶向病毒样粒子（VLP）的免疫疗法策略 Tauopathy HTAU模型中的神经炎症。最近的研究表明，一旦Tau是过度磷酸化和错误折叠，神经元倾向于将PTAU驱逐到细胞外空间，这被采取由其他神经元提高，并导致PTAU的跨神经元传播。我们做出了令人信服的发现在通往其他神经元的途中，PTAU也可以与初始触发物进行交互，以导致小胶质激活和神经炎症。但是，目前尚不清楚PTAU如何确切地诱导先天免疫激活小胶质细胞。我们的初步结果表明，神经衍生的PTAU上调小胶质细胞的可能性表面受体，例如Toll样受体（TLR），参与MyD88（一种主要TLR的关键衔接蛋白和IL-1RS），激活NF-KB和NLRP3-肠炎，并导致小胶质细胞中IL-1β的成熟。令人惊讶的是，抑制PTAU在体内，MyD88或ASC的小胶质特异性缺失，显着降低了IL-1β 成熟。有趣的是，通过基于VLP的疫苗清除PTAU可降低MyD88的表达，神经炎症， tau病理并改善记忆力。基于这些初步观察，我们假设PTAU 通过TLR/MYD88依赖性激活NF-KB-NLRP3-爆发性炎症 - IL-1β先天免疫复合物小胶质细胞的途径。靶向PTAU（通过基于VLP的免疫疗法），MyD88或IL-1R1辅助蛋白（IL- 1RACP）在不同级别的级联级别上阻止了由 tau。我们将根据三个特定目标检验该假设。在特定目标1中，我们建议确定是否 MyD88和IL-1β成熟由NLRP3-ASC-炎症途径。在特定目标2中，我们建议确定PTAU诱导的进行性NF-KB激活，神经炎症，基于MRI的结构改变和认知功能障碍是 MyD88/IL-1RACP依赖于Tauopathy的HTAU小鼠模型。最后，在特定目标3中，我们将确定是否通过基于VLP的免疫疗法阻止PTAU可减少NF-KB启动和IL-1β成熟以及恢复 HTAU小鼠的记忆。这项研究的成功结果将决定PTAU是否触发通过MyD88-NF-KB-NLRP3-ASC炎症-IL-1β途径进行神经炎症。这具有很高的意义为了开发和测试基于VLP的PTAU针对神经炎症的靶向疗法 tauopathies。