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

Tau 病理学中通过 TREM2 和外周免疫细胞调节白质损伤

• 批准号: 10623183
• 负责人: Tyler McCray
• 金额: $ 3.2万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10623183
• 关键词: Affect; Age; Age Months; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Behavior; Behavioral; Biological Assay; Biological Response Modifiers; Brain; Brain Stem; Brain region; CCL2 gene; Cause of Death; Cells; Central Nervous System; Cerebellum; Chemotaxis; Data; Dementia; Development; Disease; Disease Progression; Elderly; Electron Microscopy; Etiology; Exclusion; Extravasation; Flow Cytometry; Generations; Immune; Immune Targeting; Immune response; Immunity; Immunohistochemistry; Immunologic Receptors; In Situ; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Knowledge; Leukocytes; Link; Location; LoxP-flanked allele; Mediating; Membrane; Microglia; Modification; Mus; Myeloid Cells; Natural Immunity; Nerve Degeneration; Neurons; Outcome; Output; Pathologic; Pathology; Pathway interactions; Peripheral; Phagocytes; Phenotype; Population; Reporting; Role; Signal Pathway; Signal Transduction; Slice; Structure of choroid plexus; T-Lymphocyte; TREM2 gene; Tamoxifen; Tauopathies; Time; Variant; Western Blotting; axon injury; brain parenchyma; cell mediated immune response; genetic variant; genome wide association study; gray matter; hyperphosphorylated tau; monocyte; mouse model; neuroinflammation; novel therapeutic intervention; peripheral blood; prevent; promoter; receptor; recruit; response; tau Proteins; tau-1; transcriptome sequencing; transcriptomics; white matter; white matter damage

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.

项目摘要 阿尔茨海默病（AD）是一种不可逆的、进行性的痴呆形式，是导致死亡的主要原因 在全球全基因组关联研究已确定骨髓细胞上表达的触发受体2 （TREM 2）变体，其赋予AD风险。TREM 2是一种整合的膜受体，仅表达于 介导免疫反应的骨髓细胞。TREM 2的表达在每个CNS区域内变化， 疾病状态，在白色物质中高表达。 使用人源化tau（hTau）小鼠模型，我们的实验室已经鉴定了CD 45 hi外周细胞的输入， 其主要被募集到白色物质区域并且通常被排除在灰质区域之外。 与这些CD 45 hi细胞的浸润一致，TREM 2表达在白色物质、小脑、小脑中增加， 和脑干，主要是在12个月大的时候，这表明TREM 2和外周免疫之间的联系。 在晚期tau病理学期间的反应。有趣的是，阻止这些细胞进入脑实质 通过消除CCR 2介导的外渗加剧了白色物质内的tau病理学， 轴突损伤，但CD 45 hi细胞继续在脉络丛中积累，表明其他信号传导 参与招聘的途径。类似地，在不存在TREM 2的情况下，CD 45 hi细胞的数量增加。 减少，CD 45 hi细胞不再局限于白色物质区域，tau病理学消失 恶化了因此，我们证实TREM 2调节小鼠模型中的白色物质病理学。 通过外周免疫细胞募集的tau蛋白病。 我们将从以下几个方面来检验这一假说：1）确定表型、位置和相关基因。 在hTau和hTau; Trem 2-/-小鼠中的这些免疫群体的病理学; 2）解剖TREM 2介导的免疫细胞; 这些免疫细胞外渗到大脑中的机制，使用切片培养和无偏空间 3）使用条件转录组学以疾病进展依赖性方式调节TREM 2输入 小胶质细胞TREM 2敲除小鼠，以确定功能行为输出并将它们与 白色物质病理学作为这些免疫细胞的结果。从这些研究中获得的知识将 对于理解TREM 2调节的先天和外周免疫之间的界面是重要的， 早期和晚期阶段tau病理学的背景，并且对于开发新的 外周免疫反应的时机和调节的治疗方法，不仅针对AD，而且 更普遍的神经变性。