Modulation of White Matter Damage via TREM2 and Peripheral Immune Cells in Tau Pathologies

项目摘要 阿尔茨海默病(AD)是一种不可逆转的进行性痴呆症，是导致死亡的主要原因 全球范围内。全基因组关联研究已确定在髓系细胞上表达的触发受体2 (TREM2)变异，可增加AD的风险。TREM2是一种完整的膜受体，仅表达于 调节免疫反应的髓系细胞。TREM2在每个中枢神经系统区域的表达不同， 疾病状态，白质高表达。 使用人源化tau(HTau)小鼠模型，我们的实验室已经识别了CD45hi外周细胞的输入 它们主要被招募到白质区域，通常被排除在灰质区域之外。 与这些CD45hi细胞的浸润相一致，TREM2在白质、小脑、 和脑干，主要在12个月大的时候，这表明TREM2和外周免疫之间存在联系 在tau病理晚期的反应。有趣的是，阻止这些细胞进入脑实质 通过取消CCR2介导的外渗，加剧了白质内tau的病理，并促进了 轴突损伤，但CD45hi细胞继续聚集在脉络丛中，表明有其他信号 参与他们招募的路径。同样，在没有TREM2的情况下，CD45hi细胞的数量 减少，CD45hi细胞不再局限于白质区域，tau病理 更糟了。因此，我们假设TREM2调节脑白质病变的小鼠模型。 通过外周免疫细胞募集而引起的肌萎缩侧索硬化。 我们将在以下目标中检验这一假设：1)确定表型、位置和相关 这些免疫群体在hTau和hTau；TREM2-/-小鼠中的病理学；2)解剖TREM2介导的 用切片培养和无偏空间研究这些免疫细胞外渗到脑内的机制 转录学；3)以疾病进展依赖的方式调节TREM2输入 小胶质细胞TREM2基因敲除小鼠以确定功能行为输出并将它们与 白质病理是这些免疫细胞的结果。从这些研究中获得的知识将 了解TREM2调节的先天免疫和外周免疫之间的接口是很重要的 早期和晚期陶氏病理的背景，对小说的发展将是无价的 外周免疫反应的时机和改变的治疗方法，不仅是对AD，而且是 更广泛地说是神经退行性变。

Project Summary Alzheimer’s disease (AD) is an irreversible, progressive form of dementia and a leading cause of death globally. Genome-wide association studies have identified Triggering Receptor Expressed on Myeloid cells 2 (TREM2) variants that confer risk for AD. TREM2 is an integral membrane receptor exclusively expressed on myeloid cells that mediates immune responses. Expression of TREM2 varies within each CNS region and disease state, with high expression in white matter. Using a humanized tau (hTau) mouse model, our lab has identified the input of CD45hi peripheral cells that are recruited predominantly to white matter regions and generally excluded from gray matter regions. Coincident with infiltration of these CD45hi cells, TREM2 expression is increased in white matter, cerebellum, and brainstem, largely at 12 months of age, suggesting a connection between TREM2 and peripheral immune response during later stage tau pathology. Intriguingly, blocking entry of these cells into the brain parenchyma by abrogating CCR2-mediated extravasation exacerbates tau pathology within the white matter and promotes axonal damage, but CD45hi cells continue to accumulate in the choroid plexus indicating other signaling pathways participating in their recruitment. Similarly, in the absence of TREM2 the number of CD45hi cells decreased, the CD45hi cells no longer remained localized to white matter regions, and tau pathology was worsened. Therefore, we posit that TREM2 modulates white matter pathology in a mouse model of tauopathy via peripheral immune cell recruitment. We will examine this hypothesis in the following aims: 1) identify phenotype, location, and associated pathology of these immune populations in hTau and hTau;Trem2-/- mice; 2) dissect the TREM2-mediated mechanism of extravasation of these immune cells into the brain using slice cultures and unbiased spatial transcriptomics; 3) modulate TREM2 input in a disease-progression dependent manner using conditional microglial TREM2 knockout mice to determine the functional behavior outputs and correlate them to regions of white matter pathology as a consequence of these immune cells. The knowledge gained from these studies will be important to understanding the interface between innate and peripheral immunity modulated by TREM2 in the context of both early and late stage tau pathology and will be invaluable for the development of novel therapeutic approaches in timing and modification of peripheral immune responses, not only for AD, but neurodegeneration more generally.