The role of peripheral myeloid cells in Alzheimers disease

外周髓细胞在阿尔茨海默病中的作用

基本信息

批准号：
9311219
负责人：
Towfique Raj
金额：
$ 83.37万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311219
关键词：
Abeta clearance Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Autopsy Blood Circulation Brain Brain Diseases Candidate Disease Gene Cell Surface Receptors Cell physiology Cells Code Conflict (Psychology)Cytometry DNA Methylation Data Data Analyses Data Set Dementia Deposition Development Disease Epigenetic Process Event Functional disorder Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Genetic Variation Genome Scan Goals Human Immune Immune system Immunohistochemistry Immunologic Markers Impaired cognition Individual Inflammatory Late Onset Alzheimer Disease Lead Link Microglia Molecular Myelin Myelogenous Myeloid Cells Network-based Neurodegenerative Disorders Ontology Pathogenesis Pathology Pathway interactions Patients Peripheral Phagocytes Phenotype Process Quantitative Trait Loci Regulation Research Role Signal Transduction Stimulus Susceptibility Gene T-Lymphocyte TREM2 gene Testing Therapeutic Intervention Tissues Validation Variant Work age related aged arm base biomarker discovery blood-based biomarker case control computer based statistical methods disorder risk epigenetic variation follow-up functional genomics genetic risk factor genetic variant genome wide association study immune system function innate immune function innovation insight interest mRNA Expression macrophage methylome monocyte neuroinflammation new therapeutic target novel novel diagnostics novel therapeutic intervention peripheral blood response risk variant transcriptome uptake

项目摘要

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Recent genome scans have identified over twenty novel AD susceptibility loci, and several of these loci implicate the immune system. Our recent gene expression analyses of data from healthy young individuals have implicated 12 AD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in the primary monocytes. We have also recently identified AD risk-increasing alleles of the myeloid cell surface receptor CD33 that are associated with diminished Aβ uptake by human monocytes. Furthermore, AD GWAS signals, as well as the most strongly validated coding variants associated with AD (in APOE, TREM2 and ABCA7), coalesce around genes that are necessary for efficient phagocytic clearance of cellular debris by myeloid cells. Therefore, these loci represent excellent candidates as the first step in the cascade of molecular events that link genetic risk factors to the altered innate immune function that contributes to AD pathology. Indeed there is conflicting evidence as to the relative importance in AD pathogenesis of peripheral myeloid cells that subsequently enter the brain versus tissue resident myeloid cells such as microglia. Because of their shared ontology regulation of expression of many myeloid specific genes is likely to be shared between monocytes and microglia. Given the ease of access to blood monocytes throughout the disease process, compared to microglia that are only accessible at autopsy we propose to explore the functional consequences of commonly- occurring genetic variation on the transcriptome in peripheral monocytes from AD patients. Our central hypothesis is that peripheral monocyte-derived cells, such as macrophages and monocytes will manifest changes in gene expression of these AD susceptibility genes and other genes in the same molecular pathways that reflect the stages of AD pathophysiology. To test this hypothesis, we will characterize the transcriptome/methylome profiles from peripheral monocytes of 200 AD cases and 200 age-matched controls. This will be followed up with profiling of monocytes stimulated with anti- (myelin) and pro-inflammatory (LPS and Aβ) stimuli. Through innovative computational approaches, we will integrate various datasets from monocytes in order to identify causal drivers and molecular networks underlying AD pathogenesis such as Aβ clearance and neuroinflammation. We will also incorporate data from over 500 AD brains to assess if the monocyte-specific transcriptional networks recapitulate changes seen in the AD brains. Finally, we will perform highly multiplexed mass cytometry-based immune phenotype profiling to investigate the activation state and phagocytic capacity of monocytes. We will validate our most promising candidate genes from the functional studies in human microglia using immunohistochemistry. The proposed research is innovative because it will not only identify genetic mechanisms in peripheral monocytes which may contribute to interindividual risk for AD but may lead to the discovery of novel immune biomarkers.

阿尔茨海默氏病（AD）是一种与年龄有关的神经退行性疾病，其特征是进行性认知衰落和痴呆。最近的基因组扫描已经确定了二十多种新颖的AD敏感性局部，有几个这些基因座隐含了免疫系统。我们最近对健康年轻人数据的基因表达分析个体已经在髓样细胞功能中实现了12个AD敏感性基因，其表达相对于每种风险等位基因在主要单核细胞中发生了变化。我们最近还确定了广告风险增加的等位基因与人类单核细胞降低Aβ摄取的降解有关的髓样细胞表面受体CD33。此外，AD GWAS信号以及与AD相关的最强烈验证的编码变体（in apoe，trem2和abca7）在有效的吞噬清除所必需的基因周围结合髓样细胞的细胞碎屑。因此，这些本地代表了级联的第一步将遗传危险因素与改变的先天免疫功能联系起来的分子事件病理。确实存在相互矛盾的证据，表明外周的AD发病机理的相对重要性随后进入大脑与组织居民髓样细胞（如小胶质细胞）的髓样细胞。由于他们共同对许多髓样基因表达表达的共同本体学调节可能会在单核细胞和小胶质细胞。考虑到整个疾病过程中易于获得血液单核细胞的性能对于仅在尸检时可以使用的小胶质细胞，我们建议探索通常的功能后果来自AD患者的外周单核细胞中转录组的遗传变异。我们的中心假设是外周单核细胞衍生的细胞（例如巨噬细胞和单核细胞）会表现出基因的变化这些AD敏感性基因和其他基因在相同的分子途径中的表达 AD病理生理学的阶段。为了检验这一假设，我们将表征转录组/甲基曲线的特征来自200个AD病例和200个年龄匹配的对照的外围单核细胞。随后将进行分析用抗（髓磷脂）和促炎（LPS和Aβ）刺激的单核细胞刺激。通过创新计算方法，我们将整合单核细胞中的各种数据集，以识别因果驱动因素和 AD发病机理的基础分子网络，例如Aβ清除率和神经炎症。我们也会合并来自500多个AD大脑的数据，以评估单核细胞特异性转录网络是否概括广告大脑中看到的变化。最后，我们将执行高度多路复用的质量细胞仪免疫表型分析以研究单核细胞的激活状态和吞噬能力。我们将验证我们的使用免疫组织化学中，最有前途的候选基因来自人类小胶质细胞的功能研究。拟议的研究具有创新性，因为它不仅会识别外周单核细胞中的遗传机制可能会导致广告间风险，但可能导致发现新型免疫生物标志物。