Identifying, validating and targeting AD susceptibility networks in monocytes

项目总结/摘要 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， 通过进行性认知衰退和痴呆以及症状前积累 淀粉样蛋白病理学一些最近发现的AD易感基因位点含有基因 主要在骨髓细胞如单核细胞、巨噬细胞和巨噬细胞中表达， 小胶质细胞这表明先天免疫系统参与了AD 易感性和淀粉样病理的积累。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细胞， 小胶质细胞参与AD的病理生理学，特别是参与AD的细胞因子的积累。 淀粉样蛋白病理学我们初步的cis-eQTL分析数据来自健康的年轻人 个体在髓样细胞功能中涉及16个AD易感基因， 相对于每个危险等位基因，在单核细胞中而不是在T细胞中表达改变， 代表免疫系统的适应性手臂。因此，这些位点代表了 优秀的候选人作为级联分子事件的第一步， 导致AD病理改变的先天免疫功能的危险因素。的 拟议项目的主要目标是（1）识别和验证组件 在髓样细胞中受AD易感性基因座干扰的网络基因（2）， 了解它们对单核细胞行为的功能性影响，以及（3）识别FDA- 调节AD最有希望靶点的获批或新型小分子 在原代人单核细胞中的治疗。

Project Summary/Abstract 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.