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。AD病理学的一个重要组成部分涉及脑中淀粉样蛋白斑块的积累。最近的基因组扫描已经确定了10个新的AD易感基因座，其中几个基因座涉及晚发型AD的免疫系统。CD 33是这些基因之一;该蛋白质是在骨髓祖细胞和成熟单核细胞的表面上表达的跨膜糖蛋白，并且似乎具有组成性阻遏物功能，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上CD 33表达的增加与CD 33风险等位基因之间有很强的相关性。确定改变的CD 33表达在单核细胞的基本功能中所起的作用，将对该分子在AD病理学中的潜在作用提供重要的见解。使用三种不同的人类受试者集合，我们将表征（1）年轻健康受试者（2）症状前老年受试者和（3）AD受试者中单核细胞中CD 33基因座的功能后果。我们提出了一个多方面的方法，整合人类遗传学和人类免疫学实验在整个生命过程中，以了解CD 33基因座如何改变单核细胞的激活状态，并提高对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. !