Identifying, validating and targeting AD susceptibility networks in monocytes

描述（由申请人提供）：阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是进行性认知能力下降和痴呆，以及症状前淀粉样蛋白病理积累。最近发现的一些阿尔茨海默病易感位点包含主要在髓细胞中表达的基因，如单核细胞、巨噬细胞和小胶质细胞。这表明先天免疫系统参与了AD易感性和淀粉样蛋白病理的积累。因此，我们假设单核细胞来源的细胞，如浸润性巨噬细胞和常驻小胶质细胞参与了AD的病理生理，特别是淀粉样蛋白病理的积累。我们对健康年轻人的数据进行了初步的顺式- eqtl分析，发现髓细胞功能中有16个AD易感基因，相对于每个风险等位基因，这些基因的表达在单核细胞中发生了改变，而在T细胞中没有改变

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.