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: 10626135
• 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/10626135
• 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; Brain; Cell Surface Receptors; Cells; Clinical Trials; Data; Dependovirus; Development; Disease Progression; Feedback; Gene Activation; Gene Deletion; Genetic; Genetic study; Goals; Human; Immunologic Receptors; Impaired cognition; In Vitro; Inflammation; Injections; Knock-out; Knockout Mice; Knowledge; Lymphocyte Activation; Lymphocyte Depletion; Mediating; Mediator; 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; blood-brain barrier penetration; brain cell; brain dysfunction; cancer clinical trial; cancer immunotherapy; clinical development; clinical translation; efficacy evaluation; glial activation; in vivo; induced pluripotent stem cell; insight; mouse model; neuroinflammation; neurotoxicity; neurotransmission; 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)作为阿尔茨海默病(AD)的一种标志性病理，广泛分布于 广告大脑。NFTs的主要成分是充满神经细胞和神经胶质细胞的异常tau聚集体。 尸体。新出现的证据表明，病理性tau纤维能够触发一种自我传播的 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，脑内注射从AD脑中提取的病理性tau纤维 导致tau病理在小鼠脑内大量传播，并导致行为缺陷。然而， 阻止这种病理性tau扩散的治疗靶点尚未确定。我们第一次确定了 淋巴细胞活化基因3(LAG3)是介导病理性α突触核蛋白的重要受体的时间 变速箱。我们的初步研究进一步支持LAG3作为细胞表面受体，介导 Tau纤维的传递和tau引起的神经细胞和小胶质细胞的病理性缺陷。这些结果表明 LAG3可能作为一个新的靶点来阻止致病性tau的传播，以用于治疗开发。我们 我已经建立了两种病理性tau传播的小鼠模型，其神经元和行为都得到了验证 缺陷以及神经炎性反应。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有表达，LAG3的缺失可抑制tau神经元的增殖和 小胶质细胞激活。所有这些结果支持我们的中心假设，即LAG3是一种必不可少的受体。 神经细胞和小胶质细胞中的病理性tau，介导tau的内化、传递和肌病。现在，它 探讨LAG3在促进tau发病中的作用及治疗效果是可行的 通过基因缺失和单抗进行靶向。我们的目标是(1)确定LAG3在 介导病理性tau的内化以及由此引起的神经元和小胶质细胞反应 AD和其他疾病的发病机制，以及(2)开发一种临床可翻译的策略来抑制 LAG3介导的tau发病机制用于治疗tau病。如果成功，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 用于治疗发展。该项目还可能为人类免疫缺陷病毒的关键介体提供新的分子洞察力。 病理性tau在神经元和其他脑细胞中扩散。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再利用 抗LAG3抗体用于治疗阿尔茨海默病和其他疾病。

项目成果

Determinants of seeding and spreading of α-synuclein pathology in the brain.

• DOI: 10.1126/sciadv.abc2487
• 发表时间: 2020-11
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Henrich MT;Geibl FF;Lakshminarasimhan H;Stegmann A;Giasson BI;Mao X;Dawson VL;Dawson TM;Oertel WH;Surmeier DJ
• 通讯作者: Surmeier DJ

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications.

• DOI: 10.3390/ijms22052360
• 发表时间: 2021-02-26
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Wang L;Mao X
• 通讯作者: Mao X

Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer's disease.

• DOI: 10.4103/1673-5374.332137
• 发表时间: 2022-08
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Wang L;Mao X
• 通讯作者: Mao X

Lymphocyte Activation Gene 3 (Lag3) Contributes to α-Synucleinopathy in α-Synuclein Transgenic Mice.

• DOI: 10.3389/fncel.2021.656426
• 发表时间: 2021
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Gu H;Yang X;Mao X;Xu E;Qi C;Wang H;Brahmachari S;York B;Sriparna M;Li A;Chang M;Patel P;Dawson VL;Dawson TM
• 通讯作者: Dawson TM