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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：
9895593
负责人：
Towfique Raj
金额：
$ 82.51万
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/9895593
关键词：
Abeta clearance Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Autopsy Bayesian Network Blood Circulation Brain 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 Ontology Pathogenesis Pathway interactions 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 neurodegeneration aged arm base biomarker discovery blood-based biomarker case control disorder risk epigenetic variation follow-up functional genomics genetic risk factor genetic variant genome wide association study immune system function innate immune function innate immune mechanisms 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.

阿尔茨海默病（AD）是一种以进行性认知为特征的与年龄相关的神经退行性疾病