The role of peripheral myeloid cells in Alzheimers disease

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 衰老和痴呆症。最近的基因组扫描已经确定了20多个新的AD易感基因座，以及几个 这些基因座中的任何一个都会影响免疫系统。我们最近对健康年轻人数据的基因表达分析 个体已发现12个AD易感基因与髓系细胞功能有关，其相对每个基因的表达 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 髓系细胞表面受体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相关的最有效的编码变体(在 APOE，TREM2和ABCA7)，结合在有效吞噬清除 髓系细胞的细胞碎片。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 病理学。关于外周组织在AD发病机制中的相对重要性，确实存在相互矛盾的证据 随后进入大脑的髓系细胞与组织驻留的髓系细胞，如小胶质细胞。因为. 它们共享的对许多髓系特异基因表达的本体调控很可能是在 单核细胞和小胶质细胞。考虑到在整个疾病过程中很容易获得单核细胞，相比 对于只有在尸检时才能接触到的小胶质细胞，我们建议探索通常- AD患者外周血单核细胞转录组发生遗传变异。我们的中心假设 外周血单核细胞来源的细胞，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通路中的表达 阿尔茨海默病病理生理分期。为了验证这一假设，我们将描述转录组/甲基组的特征。 从200例AD患者和200例年龄匹配的正常对照的外周血单核细胞中提取。在此之后将对 单核细胞用抗(髓鞘)和促炎(脂多糖和Aβ)刺激。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，以确定因果驱动因素和 AD发病机制的分子网络，如Aβ清除和神经炎症。我们还将 结合来自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概括 阿尔茨海默病患者大脑的变化。最后，我们将进行高度多元化的基于质量细胞术的免疫 表型图谱研究单核细胞的活化状态和吞噬能力。我们将验证我们的 用免疫组织化学方法研究人类小胶质细胞功能的最有希望的候选基因。这个 拟议的研究具有创新性，因为它不仅将识别外周血单核细胞的遗传机制， 可能导致阿尔茨海默病的个体间风险，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.