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: 10461946
• 负责人: Xiaobo Mao
• 金额: $ 63.3万
• 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/10461946
• 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; translatable strategy; 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（NFTS）作为阿尔茨海默氏病的标志性病理（AD）广泛分布在 广告大脑。 NFT的主要成分是填充神经内神经元细胞的异常Tau聚集体 身体。新兴的证据表明，病理tau纤维能够触发自我传播 神经元和其他脑细胞的过程，导致神经退行性和神经炎症。 实验数据表明，从广告大脑中提取的颅内注射tau原纤维 导致小鼠大脑中tau病理的大量扩散并诱发行为缺陷。然而， 尚未确定阻止这种病理TAU扩散的治疗靶标。我们确定了第一个 淋巴细胞激活基因3（lag3）是介导病理α-突触核蛋白的必不可少的时间 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原纤维和病理tau诱导的神经元和小胶质细胞缺陷的传播。这些结果表明 该lag3可能是阻止致病性TAU扩散以进行治疗发育的新目标。我们 已经建立了两个病理tau传播的小鼠模型，该模型通过经过验证的神经元和行为 缺乏和神经炎症反应。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表示，lag3的耗竭可以抑制tau神经元传播和 小胶质激活。所有这些结果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tau介导tau内在化，传播和tauopathy。现在，它 可以探索lag3在促进tau发病机理和lag3的治疗效率中的作用 通过遗传缺失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tau的内在化以及随之而来的神经元和小胶质细胞反应 AD和其他Tauopath的发病机理，以及（2）制定可抑制临床翻译策略 lag3介导的tau发病机理用于治疗tauopathies。如果成功的话，这项研究的发现将 识别介导病理tau扩散并充当新型治疗靶的细胞表面受体 用于热发育。该项目还可能为对关键介体的新分子见解提供 病理tau在神经元和其他脑细胞中扩散。考虑到正在进行抗LAG3的临床试验 癌症免疫疗法的抗体，该项目的发现也将有助于重新利用这些 抗LAG3抗体用于治疗AD和其他Tauopathies。