The Role of Inflammasome Signaling in Tauopathies

炎症小体信号传导在 Tau蛋白病中的作用

• 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
• 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

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是否病理形式的tau（pTau）-一个重要的 神经退行性tau蛋白病的病理学标志，可通过MyD 88激活白细胞介素-1 β（IL-1β）， 依赖性核因子-kB（NF-kB）和NLRP 3-ASC炎性体途径引起神经炎症， 轴突和白色物质病理学、突触丧失和认知损害。我们的目标也是为了测试 一种新的pTau靶向的病毒样颗粒（VLP）的免疫治疗策略，针对pTau诱导的 在tau蛋白病的hTau模型中的神经炎症。最近的研究表明，一旦tau蛋白 由于过度磷酸化和错误折叠，神经元倾向于将pTau排出到细胞外空间， 通过其他神经元向上并导致pTau的跨神经元传播。我们有了一个引人注目的发现， 在通往其他神经元的途中，pTau也可以与小胶质细胞相互作用并作为导致小胶质细胞活化的初始触发器。 和神经炎症。然而，目前尚不清楚pTau如何确切地诱导体内的先天免疫激活。 小胶质细胞我们的初步结果表明，神经源性pTau上调小胶质细胞的可能性， 表面受体如Toll样受体（TLR）与MyD 88（一种常见于各种TLR的关键衔接蛋白）接合 和IL-1 R），激活NF-κ B和NLRP 3-ASC炎性体并导致小胶质细胞中IL-1β的成熟。 引人注目的是，体内抑制pTau，MyD 88或ASC的小胶质细胞特异性缺失， 成熟有趣的是，通过基于VLP的疫苗清除pTau减少了MyD 88表达，神经炎症， tau病理学和改善记忆。基于这些初步观察，我们假设pTau 通过TLR/MyD 88依赖性激活NF-kB-NLRP 3-ASC炎性体-IL-1β天然免疫复合物 小胶质细胞中的通路。靶向pTau（通过基于VLP的免疫疗法）、MyD 88或IL-1 R1辅助蛋白（IL-1 R1） 1 RAcP）在该级联反应的不同水平上阻断了脑炎症的前馈诱导， τ的我们将在三个具体目标下检验这一假设。在具体目标1中，我们建议确定， 来自死后人脑的不同形式的pTau通过MyD 88和IL-1β成熟触发NF-κ B引发 通过NLRP 3-ASC-炎性体途径。在具体目标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 tau蛋白病的hTau小鼠模型中的MyD 88/IL-1 RAcP依赖性。最后，在具体目标3中，我们将确定 通过基于VLP的免疫疗法阻断pTau减少了NF-kB引发和IL-1β成熟， hTau小鼠的记忆。这项研究的成功结果将决定pTau是否会触发 通过MyD 88-NF-kB-NLRP 3-ASC炎性体-IL-1β通路的神经炎症。这份意义重大的遗嘱 用于开发和测试针对神经炎症的基于VLP的pTau靶向疗法， tau蛋白病