Identifying, validating and targeting AD susceptibility networks in monocytes

描述（由申请人提供）：阿尔茨海默病（AD）是一种年龄相关的神经退行性疾病，其特征为进行性认知下降和痴呆以及淀粉样蛋白病理学的症状前积累。许多最近发现的AD易感基因座包含主要在骨髓细胞（例如单核细胞、巨噬细胞和小胶质细胞）中表达的基因。这表明先天免疫系统参与了AD易感性和淀粉样蛋白病理学的积累。因此，我们假设单核细胞衍生的细胞，如浸润性巨噬细胞以及常驻小胶质细胞参与AD的病理生理学，特别是淀粉样蛋白病理学的积累。我们对来自健康年轻个体的数据进行的初步顺式eQTL分析表明，髓系细胞功能中有16个AD易感基因，相对于每个风险等位基因，其表达在单核细胞中发生改变，而在代表AD适应性臂的T细胞中没有改变。 免疫系统因此，这些基因座代表了极好的候选者，作为将遗传风险因素与导致AD病理学改变的先天免疫功能联系起来的分子事件级联中的第一步。所提出的项目的主要目标是（1）鉴定和验证髓样细胞中受AD易感性基因座干扰的网络的组分基因（2）以了解其对单核细胞行为的功能后果和（3）鉴定FDA批准的或新型的小分子，其调节原代人单核细胞中最有希望的AD治疗靶点。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia as well as pre-symptomatic accumulation of amyloid pathology. A number of recently identified AD susceptibility loci contain genes expressed predominantly in myeloid cells, such as monocytes, macrophages and microglia. This suggests the involvement of the innate immune system in AD susceptibility and the accumulation of amyloid pathology. Therefore, we hypothesized that monocyte-derived cells, such as infiltrating macrophages as well as resident microglia are involved in the pathophysiology of AD and, particularly, in the accumulation of amyloid pathology. Our preliminary cis-eQTL analyses of data from healthy young individuals have implicated 16 AD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in monocytes and not in T cells that represent the adaptive arm of the immune system. 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. The principal goals of the proposed project are (1) to identify and validate the component genes of networks perturbed by the AD susceptibility loci in myeloid cells (2) to understand their functional consequences on monocyte behavior and (3) identify FDA- approved or novel small molecules that modulate the most promising targets for AD therapy in primary human monocytes.