Mechanism of Pathologic Tau Fibrils Neuron-to-Neuron Transmission and Neuroinflammation in Alzheimer's Disease

阿尔茨海默病中病理性 Tau 原纤维神经元间传递和神经炎症的机制

• 批准号: 10277023
• 负责人: Xiaobo Mao
• 金额: $ 63.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277023
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Antibodies; Astrocytes; Behavior; Behavioral; Binding; Blood - brain barrier anatomy; Brain; Cell Surface Receptors; Cells; Clinical Trials; Cognitive; Data; Dependovirus; Development; Disease Progression; Feedback; Gene Activation; Gene Deletion; Genetic; Genetic study; Goals; Human; Immunologic Receptors; In Vitro; Inflammation; Injections; Knock-out; Knowledge; Lymphocyte Activation; Lymphocyte Depletion; Mediating; Mediator of activation protein; Microglia; Modeling; Molecular; Monoclonal Antibodies; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Pathogenesis; Pathologic; Pathology; Phagocytosis; Pharmacologic Substance; Play; Process; Proteins; Reporting; Role; Severity of illness; Tauopathies; Therapeutic; Time; Treatment Efficacy; alpha synuclein; base; brain cell; cancer clinical trial; cancer immunotherapy; clinical development; clinical translation; clinically translatable; in vivo; induced pluripotent stem cell; insight; mouse model; neuroinflammation; neurotoxicity; new therapeutic target; novel; pre-clinical; prion-like; receptor; receptor binding; response; targeted treatment; tau Proteins; tau aggregation; tau mutation; therapeutic development; therapeutic target; therapeutically effective; transmission process; uptake

Project Summary/Abstract: Neurofibrillary tangles (NFTs) as a hallmark pathology of Alzheimer's disease (AD) are widely distributed in the AD brain. The major constituent of NFTs is abnormal tau aggregates filling the intraneuronal and glial cell body. Emerging evidence indicated that pathologic tau fibrils are capable of triggering a self-propagating process in neurons and other brain cells that leads to neurodegeneration and neuroinflammation. Experimental data have shown that intracranial injection of pathologic tau fibrils extracted from AD brains results in substantial spreading of tau pathology in mouse brains and induces behavioral deficits. However, therapeutic targets to block this pathologic tau spreading have not been identified. We identified for the first time that lymphocyte-activation gene 3 (Lag3) is an essential receptor mediating the pathologic α-synuclein transmission. Our preliminary studies further support that Lag3, as a cell surface receptor, mediates the transmission of tau fibrils and pathologic tau-induced neuronal and microglial deficits. These results suggest that Lag3 may serve as a novel target for blocking pathogenic tau spreading for therapeutic development. We have established two mouse models of pathologic tau spreading with validated neuronal and behavioral deficits as well as neuroinflammatory response. Of note, our preliminary data suggests that Lag3 protein is expressed both in neurons and microglia, and depletion of Lag3 can inhibit tau neuronal propagation and microglial activation. All these results support our central hypothesis that Lag3 is an essential receptor of pathologic tau in neurons and microglia that mediates tau internalization, transmission and tauopathy. Now, it is feasible to explore the role of Lag3 in facilitating tau pathogenesis and the therapeutic efficacy of Lag3 targeting via genetic deletion and monoclonal antibodies. Our goals are (1) to define the role of Lag3 in mediating internalization of pathologic tau and the consequent neuronal and microglial responses involved in the pathogenesis of AD and other tauopathies, and (2) to develop a clinical translatable strategy to inhibit Lag3-mediated tau pathogenesis for the treatment of tauopathies. If successful, discoveries from this study will identify a cell-surface receptor that mediates pathologic tau spreading and serve as a novel therapeutic target for therapeutic development. This project may also provide novel molecular insights into key mediators of pathologic tau spreading in neurons and other brain cells. Given the on-going clinical trials using anti-Lag3 antibodies for cancer immunotherapy, discoveries from this project will also facilitate the repurposing of these anti-Lag3 antibodies for treating AD and other tauopathies.

项目摘要/摘要： 神经原纤维缠结（NFT）作为阿尔茨海默病（AD）的标志性病理，广泛分布于 AD大脑。 NFT 的主要成分是填充神经元内和神经胶质细胞的异常 tau 聚集体 身体。新出现的证据表明，病理性 tau 原纤维能够触发自我繁殖 神经元和其他脑细胞中导致神经变性和神经炎症的过程。 实验数据表明，颅内注射从AD大脑中提取的病理性tau原纤维 导致 tau 蛋白病理学在小鼠大脑中大量扩散并诱发行为缺陷。然而， 阻止这种病理性 tau 扩散的治疗靶标尚未确定。我们首先确定了 淋巴细胞激活基因 3 (Lag3) 是介导病理性 α-突触核蛋白的重要受体的时间 传播。我们的初步研究进一步支持 Lag3 作为细胞表面受体介导 tau 原纤维的传播和病理性 tau 诱导的神经元和小胶质细胞缺陷。这些结果表明 Lag3 可能作为阻止致病性 tau 扩散的新靶标，以用于治疗开发。我们 建立了两种病理性 tau 扩散小鼠模型，并具有经过验证的神经元和行为 缺陷以及神经炎症反应。值得注意的是，我们的初步数据表明 Lag3 蛋白是 在神经元和小胶质细胞中均表达，Lag3 的缺失可以抑制 tau 神经元的增殖和 小胶质细胞激活。所有这些结果都支持我们的中心假设，即 Lag3 是 神经元和小胶质细胞中的病理性 tau 介导 tau 内化、传递和 tau 病。现在，它 探讨Lag3在促进tau发病机制中的作用以及Lag3的治疗功效是可行的 通过基因删除和单克隆抗体进行靶向。我们的目标是 (1) 定义 Lag3 在 介导病理性 tau 蛋白的内化以及随后参与的神经元和小胶质细胞反应 AD 和其他 tau蛋白病的发病机制，以及 (2) 开发临床可转化策略来抑制 Lag3 介导的 tau 蛋白发病机制用于治疗 tau 蛋白病。如果成功的话，这项研究的发现将 鉴定介导病理性 tau 扩散的细胞表面受体并作为新的治疗靶点 用于治疗开发。该项目还可能为关键介质提供新颖的分子见解 tau 蛋白在神经元和其他脑细胞中病理性扩散。鉴于正在进行的使用抗 Lag3 的临床试验 用于癌症免疫治疗的抗体，该项目的发现也将促进这些抗体的重新利用 用于治疗 AD 和其他 tau 病的抗 Lag3 抗体。