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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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 大脑中 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。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。我们尚未确定阻止这种病理性 tau 扩散的治疗靶标。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我们的初步研究进一步支持 Lag3 作为细胞表面受体介导这些结果表明 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。 Lag3 可能作为阻止致病性 tau 扩散的新靶标，以用于治疗开发。建立了两种病理性 tau 扩散小鼠模型，并经过验证的神经和行为值得注意的是，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 神经元的增殖和所有这些结果都支持我们的中心假设，即 Lag3 是一种重要的受体。神经元和小胶质细胞中的病理性 tau 介导 tau 内化、传输和 tau 病。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治疗我们的目标是 (1) 明确 Lag3 在其中的作用。介导病理性 tau 蛋白的内化以及随后参与的神经和小胶质细胞反应 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，这项研究的发现将会得到证实。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该项目还可以为关键介质提供新的分子见解。鉴于正在进行的使用抗 Lag3 的临床试验，tau 蛋白在神经元和其他脑细胞中的病理性扩散。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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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

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