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.

项目概要/摘要： 神经元缠结（NFT）作为阿尔茨海默病（AD）的标志性病理学广泛分布于阿尔茨海默病（AD）的神经系统中。 AD大脑。NFTs的主要成分是神经元内和神经胶质细胞内异常的tau聚集体 身体新出现的证据表明，病理性tau纤维能够触发自我传播， 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，将从AD大脑中提取的病理性tau纤维注入颅内 导致小鼠脑中tau病变的大量扩散并诱导行为缺陷。然而，在这方面， 还没有鉴定出阻断这种病理性tau扩散的治疗靶点。我们确定了第一个 淋巴细胞激活基因3（Lag 3）是介导病理性α-突触核蛋白的重要受体的时间 传输我们的初步研究进一步支持了Lag 3作为细胞表面受体，介导了 tau纤维的传递和病理性tau诱导的神经元和小胶质细胞缺陷。这些结果表明 Lag 3可以作为阻断致病性tau扩散的新靶点用于治疗开发。我们 已经建立了两种病理性tau蛋白扩散的小鼠模型， 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，Lag 3蛋白是 在神经元和小胶质细胞中表达，并且Lag 3的耗尽可以抑制tau神经元的增殖， 小胶质细胞激活。所有这些结果都支持我们的中心假设，即Lag 3是一种必需的受体， 神经元和小胶质细胞中的病理性tau，其介导tau内化、传递和tau病变。现在 探讨Lag 3在促进tau蛋白发病中的作用以及Lag 3的治疗效果是可行的 通过基因缺失和单克隆抗体进行靶向。我们的目标是（1）定义Lag 3在 介导病理性tau蛋白的内化以及随后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）开发临床可转化的策略，以抑制 用于治疗tau蛋白病的Lag 3介导的tau发病机制。如果成功，这项研究的发现将 鉴定介导病理性tau扩散并作为新治疗靶点的细胞表面受体 用于治疗发展。该项目还可能为研究细胞凋亡的关键介质提供新的分子见解。 病理性tau蛋白在神经元和其他脑细胞中扩散。鉴于正在进行的使用抗Lag 3的临床试验 癌症免疫疗法的抗体，该项目的发现也将促进这些抗体的重新利用。 用于治疗AD和其它tau蛋白病的抗-Lag 3抗体。