Neuroprotective function of microglial TREM2 in TDP43-related neurodegeneration

小胶质细胞TREM2在TDP43相关神经变性中的神经保护功能

基本信息

批准号：
9975271
负责人：
Long-Jun Wu
金额：
$ 23.85万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975271
关键词：
ALS patients Address Adopted Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animals Binding Brain Brain imaging Cells Clinical Data Disease Disease Progression Goals Human Intervention Link Mediating Microglia Modeling Molecular Morphology Motor Mus Nature Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neurons Nuclear Pathologic Pathology Phagocytes Phagocytosis Phenotype Play Process Proteins RNA-Binding Proteins Risk Rodent Model Role Signal Pathway Signal Transduction Slice Surface TREM2 gene Testing Transgenic Organisms Variant Viral confocal imaging density epidemiology study frontotemporal degeneration improved in vivo imaging migration motor disorder motor neuron degeneration mouse model nervous system disorder neuron loss neuroprotection neurotoxicity novel overexpression population based protein TDP-43 protein aggregation receptor response two-photon

项目摘要

PROJECT SUMMARY Studies using rodent models of amyotrophic lateral sclerosis (ALS) demonstrate microglia are neuroprotective during the early stages of the disease. However, the underlying molecular mechanisms are still largely unknown. Triggering receptor expressed on myeloid cell 2 (TREM2) play crucial roles in microglial proliferation, migration, and phagocytosis. TREM2 variants are linked to increased risk for neurodegenerative diseases, including Alzheimer’s disease and ALS. Thus, here we will investigate the how TREM2 mediates microglia neuroprotective effects in ALS-like proteinopathy induced by viral overexpression of TAR-DNA binding protein 43 kDa (TDP-43) and transgenic TDP-43 mouse models. Our preliminary data indicate that TDP-43 overexpression results in microglia activation in mice. We also observed that reactive microglia interact with TDP-43 positive neurons. More interestingly, TREM2 deficiency leads to more severe neuronal loss, motor dysfunction and lower survival induced by TDP- 43 overexpression. Therefore, we hypothesize that TREM2 mediates microglial neuroprotection by sensing and phagocytosing TDP-43 during ALS-like motor neuron degeneration. We will test this hypothesis in the following two Aims: Aim 1: Determine how TREM2 mediates microglial response to TDP-43 proteinopathy. In this aim, we will (a) assess how TREM2 deficiency affects microglial response to TDP-43-induced pathology by confocal imaging of brain slices and two-photon in vivo imaging of live brain. Then we will (b) test whether microglial response occurs through direct binding of TDP-43 to TREM2 and whether such binding activates TREM2 and its signaling pathways. According to our hypothesis, we predict that microglial responsiveness to TDP-43 pathology is through TREM2 and downstream signaling. Aim 2: Determine how TREM2 exerts microglial neuroprotection in TDP-43 proteinopathy. In this aim, we will (a) assess neuronal loss and motor dysfunction as well as the level of TDP-43 proteinopathy to investigate the function of microglial TREM2 in neuroprotection after TDP-43 overexpression. Furthermore, we will (b) use in vivo imaging to determine whether microglial TREM2 facilitates TDP-43 protein clearance and thus protect against spread of the TDP-43 pathology. According to our hypothesis, we predict that microglial TREM2 is neuroprotection in TDP-43 proteinopathy through promoting phagocytic clearance of TDP-43. The current study is the first attempt to study the causal link between microglial TREM2 and TDP-43 proteinopathy in ALS-like neurodegeneration. The mechanism may also serve as a common model to address the function of microglia in TDP-43 related neurological diseases, such as frontotemporal degeneration and Alzheimer’s disease.

项目概要使用肌萎缩侧索硬化症 (ALS) 啮齿动物模型进行的研究表明，小胶质细胞然而，其潜在的分子机制在疾病的早期阶段具有神经保护作用。骨髓细胞 2 上表达的触发受体 (TREM2) 在很大程度上仍不清楚。小胶质细胞增殖、迁移和吞噬作用与增加的风险有关。神经退行性疾病，包括阿尔茨海默氏病和 ALS，因此，我们将在此进行研究。 TREM2如何介导病毒诱导的ALS样蛋白病中小胶质细胞的神经保护作用 TAR-DNA 结合蛋白 43 kDa (TDP-43) 和转基因 TDP-43 小鼠模型的过表达。我们的初步数据表明 TDP-43 过度表达会导致小鼠小胶质细胞激活。还观察到反应性小胶质细胞与 TDP-43 阳性神经元相互作用，更有趣的是，TREM2。缺乏会导致更严重的神经元损失、运动功能障碍和 TDP- 引起的生存率降低 43 过表达因此，我们发现 TREM2 通过介导小胶质细胞神经保护。在 ALS 样运动神经元变性过程中感知和吞噬 TDP-43 我们将对此进行测试。假设有以下两个目标：目标 1：确定 TREM2 如何介导小胶质细胞对 TDP-43 蛋白病的反应。为此，我们将 (a) 评估 TREM2 缺陷如何影响小胶质细胞对 TDP-43 诱导的反应然后我们将通过脑切片共焦成像和活体脑双光子活体成像进行病理学。 (b) 测试小胶质细胞反应是否通过 TDP-43 与 TREM2 直接结合而发生，以及是否根据我们的假设，这种结合会激活 TREM2 及其信号通路。小胶质细胞对 TDP-43 病理学的反应是通过 TREM2 和下游信号传导实现的。目标 2：确定 TREM2 如何在 TDP-43 蛋白病中发挥小胶质细胞神经保护作用。为此，我们将 (a) 评估神经元损失和运动功能障碍以及 TDP-43 水平蛋白病研究小胶质细胞 TREM2 在 TDP-43 后神经保护中的功能此外，我们将 (b) 使用体内成像来确定小胶质细胞 TREM2 是否过度表达。促进 TDP-43 蛋白清除，从而防止 TDP-43 病理学扩散。根据我们的假设，我们预测小胶质细胞 TREM2 在 TDP-43 中具有神经保护作用通过促进 TDP-43 的吞噬细胞清除而产生蛋白质病。目前的研究是研究小胶质细胞 TREM2 和 TREM2 之间因果关系的首次尝试。 TDP-43蛋白病在ALS样神经变性中也可能是一种常见的机制。模型来解决小胶质细胞在 TDP-43 相关神经系统疾病中的功能，例如额颞叶退化和阿尔茨海默病。