The role of peripheral myeloid cells in Alzheimers disease

阿尔茨海默病（Alzheimer's disease，AD）是一种与年龄相关的神经退行性疾病，以进行性认知功能障碍为特征 衰退和痴呆。最近的基因组扫描已经确定了二十多个新的AD易感基因座， 与免疫系统有关我们最近对健康年轻人的基因表达数据进行了分析 个体涉及12个AD易感基因在骨髓细胞功能，其表达，相对于每个 风险等位基因在初级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CD 33与人单核细胞Aβ摄取减少相关。 此外，AD GWAS信号以及与AD相关的最强验证的编码变体（在 APOE、TREM 2和ABCA 7），结合在对有效的吞噬清除所必需的基因周围。 细胞碎片被髓样细胞吞噬。因此，这些位点代表了级联反应中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，有相互矛盾的证据，在AD发病机制的相对重要性，周围 随后进入脑的髓样细胞与组织驻留的髓样细胞如小胶质细胞。因为 它们共享的对许多髓样特异性基因表达的本体调节可能在 单核细胞和小胶质细胞。考虑到在整个疾病过程中容易获得血液单核细胞， 对于只有在尸检中才能接触到的小胶质细胞，我们建议探索常见的功能性后果- AD患者外周血单核细胞转录组发生遗传变异。我们的核心假设 外周单核细胞衍生的细胞，如巨噬细胞和单核细胞将表现出基因改变， 这些AD易感基因和其他基因在相同的分子途径中的表达，反映了AD的发病机制。 AD病理生理学的阶段。为了验证这一假设，我们将描述转录组/甲基化组谱， 200例AD患者和200例年龄匹配的对照者的外周血单核细胞。这将是后续的分析， 用抗（髓鞘）和促炎（LPS和Aβ）刺激刺激单核细胞。通过创新 通过计算方法，我们将整合来自单核细胞的各种数据集，以确定因果驱动因素， AD发病机制的分子网络，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，以评估单核细胞特异性转录网络是否重演 在AD大脑中看到的变化。最后，我们将进行高度多重质量细胞计数为基础的免疫 表型分析以研究单核细胞的活化状态和吞噬能力。我们将验证我们的 最有希望的候选基因的功能研究，在人类小胶质细胞使用免疫组织化学。的 所提出的研究是创新的，因为它不仅将确定外周单核细胞的遗传机制， 可能有助于AD的个体间风险，但可能导致新的免疫生物标志物的发现。

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.