Altered monocyte function in relation to the CD33 Alzheimers disease locus

与 CD33 阿尔茨海默病基因座相关的单核细胞功能改变

• 批准号: 8549085
• 负责人: Elizabeth M Bradshaw
• 金额: $ 33.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549085
• 关键词: Accounting; Address; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Brain; Cell surface; Cells; Cessation of life; Cleaved cell; Collaborations; Collection; Complement Receptor; Data; Dementia; Dextrans; Diagnosis; Disease susceptibility; Early Onset Familial Alzheimer' s Disease; Elderly; Functional RNA; Gene Expression Profile; Genes; Genetic Transcription; Genome Scan; Genotype; Glycoproteins; Haplotypes; Human; Human Genetics; Human Genome; ITIM; Image; Immune; Immune system; Immunology; Impaired cognition; Individual; Inflammatory; International; Label; Late Onset Alzheimer Disease; Lectin; Life; Life Cycle Stages; Ligands; Maps; Mediating; Metabolism; Microglia; Mutation; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Natural Immunity; Neuraxis; Neurodegenerative Disorders; Pathologic; Pathology; Patients; Peripheral; Phagocytosis; Phenotype; Pittsburgh Compound-B; Play; Positron-Emission Tomography; Predisposition; Production; Prospective Studies; Protein Isoforms; Proteins; RNA; RNA Sequences; Radio; Risk; Role; Senile Plaques; Surface; Testing; Time; Transcript; age related; amyloid pathology; amyloid precursor protein ligand; cohort; cytokine; dextran; familial Alzheimer disease; genetic variant; genome-wide; human subject; insight; monocyte; novel; presenilin-1; programs; research study; response; trait

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. !

描述(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，特征是进行性认知能力下降和痴呆症。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。最近的基因组扫描发现了10个新的AD易感基因座，其中几个与晚发性AD的免疫系统有关。CD33是这些基因中的一个；该蛋白是一种表达在髓系祖细胞和成熟单核细胞表面的跨膜糖蛋白，似乎具有结构性抑制功能，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CD33表达增加与CD33风险等位基因有很强的相关性。确定CD33的表达变化在单核细胞的基本功能中所起的作用，将对该分子在AD病理中的潜在作用提供重要的见解。利用三组不同的人类受试者，我们将描述(1)较年轻的健康受试者(2)无症状的老年受试者和(3)AD受试者单核细胞CD33基因位点的功能后果。我们提出了一种多方面的方法，将整个生命过程中的人类遗传学和人类免疫学实验结合起来，以了解CD33基因座如何改变单核细胞的激活状态，并增强对AD的易感性。好了！