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（由申请人提供）：本申请集中于描绘共同居住在骨髓细胞中的两种不同的骨髓细胞谱系的生物学功能差异。 阿尔茨海默病（AD）与大脑中的先天免疫系统这一器官共同构成。我们提供的初步数据表明，斑块相关的髓样细胞，这是历史上被认为是大脑居民小胶质细胞，实际上是来自外周血单核细胞浸润的AD脑，随后获得某些功能与居民小胶质细胞共享。值得注意的是，单核细胞侵入脑的能力依赖于Trem 2表达。Trem 2的变异形式大大增加了AD的风险。浸润性单核细胞是主要的斑块相关细胞类型，并表现出稳健的促炎表型，但不能产生针对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不会在斑块上积累，并且在不存在TREM 2表达的情况下具有“替代活化”表型。这一应用源于对不同髓系细胞如何参与疾病过程的根本性反思，新数据表明这涉及两种截然不同的反应类型。髓样细胞的表型状态受II型核受体的相关家族的调节，所述II型核受体充当其表型的主调节剂，抑制炎性基因表达并促进组织修复和吞噬作用。本申请的主要目的是确定核受体激动剂在AD发病机制中的有益作用是否源于这些药物对浸润单核细胞的选择性作用，促进它们进入脑内并在脑内起作用，和/或促进驻留小胶质细胞中的抗炎组织修复表型。目的1的主要目标是使用在血源性炎性单核细胞中选择性表达荧光标记物的当代遗传小鼠模型，以明确地建立斑块相关细胞的外周起源，并确定核受体活化对其进入AD脑中并持续存在的影响。目的2的主要目的是确定不同谱系的单核细胞和小胶质细胞是否赋予不同的基因表达谱，以及核受体激活是否激发相同或不同的转录反应。此外，每种核受体的激活都能使脑中的髓样细胞转化为“替代激活”表型。我们的目标是确定一组基因，这些基因被负责表型转换的核受体共同激活。在目标3中，我们将通过在5XFAD小鼠的单核细胞或小胶质细胞中灭活RXRα（常见的II型核受体亚基）来消除核受体作用，从而测试核受体调节基因在两个谱系中的正常作用，并确定它们对改善AD发病机制的贡献。