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.

项目总结 使用肌萎缩侧索硬化症(ALS)啮齿动物模型的研究表明，小胶质细胞 在疾病的早期阶段进行神经保护。然而，潜在的分子机制 在很大程度上仍然不为人知。触发髓样细胞上表达的受体2(TREM2)在血管紧张素转换酶中的作用 小胶质细胞的增殖、迁移和吞噬作用。TREM2变异与增加的风险有关 神经退行性疾病，包括阿尔茨海默病和肌萎缩侧索硬化。因此，在这里我们将调查 TREM2如何在病毒诱导的ALS样蛋白病中介导小胶质细胞的神经保护作用 TDP-43过表达及转基因TDP-43小鼠模型 我们的初步数据表明，TDP-43过表达会导致小鼠小胶质细胞激活。我们 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TDP可导致更严重的神经元丢失、运动功能障碍和低存活率。 43.过度表达。因此，我们假设TREM2通过以下途径介导小胶质细胞的神经保护 肌萎缩侧索硬化症样运动神经元变性过程中TDP-43的感应和吞噬。我们将对此进行测试 假设有以下两个目的： 目的1：确定TREM2如何介导小胶质细胞对TDP-43蛋白病变的反应。 为此，我们将(A)评估TREM2缺乏如何影响小胶质细胞对TDP-43诱导的反应 脑切片共聚焦成像和活体脑双光子成像的病理学。那我们就会 (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 这种结合激活了TREM2及其信号通路。根据我们的假设，我们预测 小胶质细胞对TDP-43病理的反应是通过TREM2及其下游信号通路实现的。 目的：探讨TREM2在TDP-43蛋白病中对小胶质细胞的保护作用。 在这一目标中，我们将(A)评估神经元丢失和运动功能障碍以及TDP-43的水平 蛋白病研究TDP-43后小胶质细胞TREM2在神经保护中的作用 过度表达。此外，我们将(B)使用活体成像来确定小胶质细胞TREM2 促进TDP-43蛋白的清除，从而防止TDP-43病理的传播。 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的吞噬清除而引起的蛋白质病。 目前的研究是首次尝试研究小胶质细胞TREM2和TREM2之间的因果联系。 肌萎缩侧索硬化症样神经变性中的TDP-43蛋白病变。该机制也可以作为公共的 小胶质细胞在TDP-43相关神经疾病中的功能模型，如 额颞部退化和阿尔茨海默病。