Altered monocyte function in relation to the CD33 Alzheimers disease locus

描述（由申请人提供）：阿尔茨海默病（AD）是一种以进行性认知能力下降和痴呆为特征的与年龄相关的神经退行性疾病。AD病理的一个重要组成部分与大脑中淀粉样斑块的积累有关。最近的基因组扫描已经确定了10个新的阿尔茨海默病易感位点，其中一些位点与晚发型阿尔茨海默病的免疫系统有关。CD33就是其中一种基因；该蛋白是一种在骨髓祖细胞和成熟单核细胞表面表达的跨膜糖蛋白，似乎具有组成抑制功能，抑制单核细胞促炎细胞因子的产生。有趣的是，我们的初步数据显示单核细胞中CD33表达的增加与CD33风险等位基因有很强的相关性。确定CD33表达改变在单核细胞基本功能中的作用，将为该分子在阿尔茨海默病病理中的潜在作用提供重要见解。使用三种不同的人类受试者，我们将描述CD33位点在单核细胞中的功能后果(1)年轻健康受试者(2)症状前老年受试者和(3)AD患者。我们提出了一种多方面的方法，将人类遗传学和人类免疫学实验整合到整个生命过程中，以了解CD33位点如何改变单核细胞的激活状态并增强对AD的易感性。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. An important component of AD pathology relates to the accumulation of amyloid plaques in the brain. Recent genome scans have identified ten novel AD susceptibility loci, and several of these loci implicate the immune system in late-onset AD. CD33 is one of these genes; the protein is a transmembrane glycoprotein expressed on the surface of myeloid progenitor cells and mature monocytes and appears to have a constitutive repressor function, subduing monocyte pro- inflammatory cytokine production. Interestingly, our preliminary data shows a strong correlation of increased CD33 expression on monocytes and the CD33 risk alele. Determining the role that altered CD33 expression plays in the basic functions of monocytes, will give important insights into the potential role of this molecule in AD pathology. Using three different collections of human subjects, we will characterize the functional consequences of the CD33 locus in monocytes in (1) younger healthy subjects (2) presymptomatic older subjects, and (3) subjects with AD. We propose a multifaceted approach integrating human genetic and human immunology experiments throughout the life course to understand how the CD33 locus alters the state of activation in monocytes and enhances susceptibility to AD.