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

• 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
• 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' s Disease; Alzheimer' 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

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）是一种与年龄相关的神经退行性疾病，其特征是进行性认知障碍 衰退和痴呆。最近的基因组扫描已识别出二十多个新的 AD 易感位点，以及几个 这些位点涉及免疫系统。我们最近对健康年轻人的数据进行基因表达分析 个人发现 12 个 AD 易感基因与骨髓细胞功能有关，其表达相对于每个 风险等位基因在原代单核细胞中发生改变。我们最近还发现了 AD 风险增加的等位基因 骨髓细胞表面受体 CD33 与人类单核细胞 Aβ 摄取减少有关。 此外，AD GWAS 信号以及与 AD 相关的经过最严格验证的编码变体（在 APOE、TREM2 和 ABCA7），结合在有效吞噬清除所必需的基因周围 骨髓细胞产生的细胞碎片。因此，这些基因座代表了作为级联第一步的优秀候选者 将遗传风险因素与导致 AD 的先天免疫功能改变联系起来的分子事件 病理。事实上，关于外周血管疾病在 AD 发病机制中的相对重要性，存在相互矛盾的证据。 随后进入大脑的骨髓细胞与小胶质细胞等组织驻留的骨髓细胞。由于 他们对许多骨髓特异性基因表达的共同本体调节可能是共享的 单核细胞和小胶质细胞。鉴于在整个疾病过程中容易获得血液​​单核细胞，比较 对于只有在尸检时才能接触到的小胶质细胞，我们建议探索常见的功能后果： AD 患者外周单核细胞转录组发生遗传变异。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变化 这些 AD 易感基因和其他基因在同一分子途径中的表达反映了 AD 病理生理学的阶段。为了检验这个假设，我们将表征转录组/甲基化组概况 来自 200 个 AD 病例和 200 个年龄匹配对照的外周单核细胞。随后将进行分析 用抗（髓磷脂）和促炎（LPS 和 Aβ）刺激刺激的单核细胞。通过创新 计算方法，我们将整合来自单核细胞的各种数据集，以识别因果驱动因素和 AD 发病机制的分子网络，例如 Aβ 清除和神经炎症。我们还将 整合来自 500 多个 AD 大脑的数据来评估单核细胞特异性转录网络是否重演 AD 大脑中观察到的变化。最后，我们将进行高度多重的基于质谱流式细胞术的免疫分析 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 使用免疫组织化学对人类小胶质细胞进行功能研究的最有希望的候选基因。这 拟议的研究具有创新性，因为它不仅可以识别外周单核细胞的遗传机制， 可能会增加个体间患 AD 的风险，但可能会导致新的免疫生物标志物的发现。