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

• 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
• 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' 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

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.

项目摘要 使用肌萎缩侧索硬化症（ALS）啮齿动物模型的研究表明， 在疾病的早期阶段具有神经保护作用。然而，潜在的分子机制 仍然是未知的。髓样细胞触发受体2（TREM 2）在骨髓细胞凋亡中发挥重要作用。 小胶质细胞增殖、迁移和吞噬作用。TREM 2变异与以下风险增加有关： 神经退行性疾病，包括阿尔茨海默病和ALS。因此，在这里，我们将调查 TREM 2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）的过表达和转基因TDP-43小鼠模型。 我们的初步数据表明TDP-43过表达导致小鼠小胶质细胞活化。我们 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，TREM 2 缺乏导致更严重的神经元丢失，运动功能障碍和TDP诱导的较低存活率， 43例过度表达。因此，我们假设TREM 2介导小胶质细胞的神经保护作用， 在ALS样运动神经元变性期间感知和吞噬TDP-43。我们将测试这个 假设在以下两个目标： 目的1：确定TREM 2如何介导小胶质细胞对TDP-43蛋白质病的反应。 在这个目标中，我们将（a）评估TREM 2缺陷如何影响小胶质细胞对TDP-43诱导的细胞凋亡的反应。 通过脑切片的共焦成像和活脑的双光子体内成像来进行病理学研究。那么我们将 (b)测试是否通过TDP-43与TREM 2的直接结合发生小胶质细胞反应，以及是否 这种结合激活TREM 2及其信号传导途径。根据我们的假设，我们预测 小胶质细胞对TDP-43病理学的反应是通过TREM 2和下游信号传导。 目的2：确定TREM 2如何在TDP-43蛋白病中发挥小胶质细胞神经保护作用。 在这个目标中，我们将（a）评估神经元损失和运动功能障碍以及TDP-43水平， 研究小胶质细胞TREM 2在TDP-43后神经保护中的功能 过度表达此外，我们将（B）使用体内成像来确定小胶质细胞TREM 2是否与肿瘤细胞的增殖有关。 促进TDP-43蛋白清除，从而防止TDP-43病变的扩散。 根据我们的假设，我们预测小胶质细胞TREM 2在TDP-43中具有神经保护作用， 通过促进TDP-43的吞噬清除而抑制蛋白质病。 目前的研究是第一次尝试研究小胶质细胞TREM 2和 ALS样神经变性中的TDP-43蛋白质病该机制还可以作为一个共同的 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 额颞叶退化症和阿尔茨海默病