Actions of Nuclear Receptors on TREM2+ myeloid cells and microglia in AD brain

核受体对 AD 脑中 TREM2 髓系细胞和小胶质细胞的作用

• 批准号: 9104448
• 负责人: GARY E. LANDRETH
• 金额: $ 33.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2016-10-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104448
• 关键词: Agonist; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Base of the Brain; Biological; Biology; Blood; Blood Circulation; Brain; CCL2 gene; CD36 gene; Cell Lineage; Cell Surface Receptors; Cell surface; Cells; Cognition; Complex; Data; Deposition; Disease; Drug effect disorder; Endothelium; Excision; Exhibits; Family; Gene Expression; Genes; Genetic; Genetic study; Goals; Human Genetics; Immune; Immune response; Immune system; Infiltration; Inflammation; Inflammatory; Invaded; Ligands; Maintenance; Mediating; Memory; Metabolism; Microglia; Molecular Profiling; Mus; Myelogenous; Myeloid Cells; Nuclear Receptors; Organ; PPAR delta; PPAR gamma; Pathogenesis; Pathology; Peripheral; Phagocytosis; Pharmaceutical Preparations; Phenotype; Population; Process; RXR; Receptor Activation; Receptor Signaling; Regulation; Role; Testing; Tissues; Variant; activating transcription factor; base; cell type; chemokine; cohort; gene induction; genetic variant; high risk; improved; macrophage; monocyte; mouse model; novel therapeutic intervention; peripheral blood; public health relevance; receptor; repaired; response; risk variant; selective expression; tissue repair; transcription factor

 DESCRIPTION (provided by applicant): This application is focused on the delineation of the functional differences in the biology of two distinct lineages of myeloid cells which coinhabit the Alzheimer's disease (AD) brain and together constitute the innate immune system in this organ. We provide preliminary data demonstrating that plaque-associated myeloid cells, which were historically presumed to be brain resident microglia, are in fact derived from peripheral blood borne monocytes which infiltrate the AD brain and subsequently acquire certain features shared with the resident microglia. Remarkably, the ability of monocytes to invade the brain is reliant upon Trem2 expression. Variant forms of Trem2 confer greatly increased risk for AD. It is the infiltrating monocytes which are the predominant plaque-associated cell type and exhibit a robust proinflammatory phenotype but are unable to mount an effective phagocytic response directed to amyloid deposits in the AD brain. In contrast, the endogenous microglia do not appear to accumulate on plaques and in the absence of TREM2 expression have an `alternative activation' phenotype. This application arises from a fundamental rethinking of how the different myeloid lineage cells participate in the disease process, which new data suggest involves two quite distinct types of responses. The phenotypic status of myeloid cells is subject to regulation by a related family of type II nuclear receptors which serve as master regulators of their phenotype, suppressing inflammatory gene expression and promoting tissue repair and phagocytosis. This application has as a primary goal to ascertain if the salutary effects of nuclear receptor agonists in AD pathogenesis arise from the selective action of these drugs on either the infiltrating monocytes, promoting their entry and actions within the brain, and /or promoting an anti-inflammatory, tissue repair phenotype in resident microglia. The principal goal of Aim 1 is to use contemporary genetic mouse models that selectively express fluorescent markers in blood borne inflammatory monocytes to definitively establish the peripheral origins of the plaque-associated cells and to determine the effect of nuclear receptor activation on their entry and persistence in the AD brain. The primary objective of Aim 2 is to ascertain if the different lineages of monocytes and microglia confer different gene expression profiles and if nuclear receptor activation elicits the same or different transcriptional responses. Moreover, activation of each of the nuclear receptors elicits the conversion of myeloid cells in the brain ino an `alternative activation' phenotype. Our objective is to identify a panel of genes that are activated in common by the nuclear receptors that are responsible for the phenotypic conversion. In Aim 3, we will test the normal roles of nuclear receptor-regulated genes in the two lineages by abrogating nuclear receptor action by inactivating RXRα, the common type II nuclear receptor subunit, in either monocytes or in microglia in the 5XFAD mice and determine their contributions to ameliorating AD pathogenesis.

 描述（由应用程序提供）：此应用集中于描述髓样细胞两个不同谱系的生物学功能差异，这些骨细胞共同存在 阿尔茨海默氏病（AD）大脑，共同构成了该器官中的先天免疫系统。我们提供了初步数据，表明与历史上认为是脑居民小胶质细胞的斑块相关的髓样细胞实际上是源自周围血液出生的单核细胞，这些单核细胞渗入AD大脑，然后获得与常驻微胶质细胞共享的某些特征。值得注意的是，单核细胞侵入大脑的能力依赖于TREM2表达。 TREM2会议的变体形式大大增加了AD的风险。它是浸润的单核细胞，是主要的斑块相关细胞类型，表现出强大的促炎表型，但无法安装针对AD脑中淀粉样蛋白沉积物的有效吞噬反应。相比之下，内源性小胶质细胞似乎没有在斑块上积聚，而在没有TREM2表达的情况下具有“替代激活”表型。该应用源于对不同髓样谱系细胞如何参与疾病过程的基本重新思考，新数据表明，这涉及两种完全不同的反应。髓样细胞的表型状态受到II型核接收器的相关家族的调节，该家族是其表型的主要调节剂，抑制炎症基因表达并促进组织修复和吞噬作用。该应用作为AIM 1的主要目标是使用现代遗传小鼠模型，该模型在血液出生的炎症单核细胞中有选择性地表达荧光标记，以确定建立与斑块相关细胞的外围起源，并确定核受体激活对其在广告大脑中的进入和持久性的效果。目标2的主要目的是确定单核细胞和小胶质细胞会议的不同谱系是否不同的基因表达谱以及核受体激活是否引起相同或不同的转录反应。此外，每个核受体的激活都会引起大脑中髓样细胞的转化，并引起“替代激活”表型。我们的目标是确定由负责表型转化的核接收器所激活的一系列基因。在AIM 3中，我们将通过灭活5xFAD小鼠中的单核细胞或小胶质细胞中的普通II型核接收器亚基RXRα（在单核细胞中或小胶质细胞中消除RXRα）来测试两个谱系中核接收器调节的基因的正常作用，并确定其对放松促进发病机制的贡献。