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APOE4 dependent regulation of CSF Complement Pathway Activation in the development of Alzheimer's Disease

APOE4 依赖性调节脑脊液补体通路激活在阿尔茨海默病的发展过程中

基本信息

批准号：
10871775
负责人：
Miles Berger
金额：
$ 40.22万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10871775
关键词：
Address Administrative Supplement Adult Adult Children Age Age Distribution Aging Aliquot Alleles Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease risk American Amyloid beta-Protein Anesthetics Apolipoprotein E Bacteria Bathing Binding Biological Assay Biology Brain Caring Carrier Proteins Cell Surface Receptors Cells Cerebrospinal Fluid Cheek structure Chemicals Cholesterol Clinical Code Complement Complement Activation Complex Critiques DNA Data Dementia Development Disease Drug Targeting Eating Education Elderly Ensure Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Europe Frequencies Gene Dosage Genes Genetic Genotype Goals Homozygote Human Immune Indiana Individual Inherited Late Onset Alzheimer Disease Life Style Liquid substance Longevity Mass Spectrum Analysis Measures Memory Methods Neurofibrillary Tangles Neurons Outcome Parents Pathology Pathway interactions Persons Population Protein Subunits Proteins Proteomics Race Registries Regulation Research Risk Role Sample Size Sampling Senile Plaques Set protein Signal Transduction Spain Spinal Cord Spinal Puncture Swab Symptoms Synapses Thinking United States National Institutes of Health Universities Washington Wisconsin Work aged apolipoprotein E-3 apolipoprotein E-4 biobank cohort complement pathway genetic risk factor genetic variant neuropathology prevent recruit repository sex skills tau Proteins tau-1 trait virtual young adult

项目摘要

Dementia is a common disorder that increases in frequency in the elderly. Dementia is a progressive loss of thinking and memory skills that eventually results in an inability to care for oneself and to live independently. The most common cause of dementia in older Americans is Alzheimer’s Disease, which develops as a result of multiple lifestyle/environmental factors and inherited or familial causes. Many familial traits (such as the risk of developing Alzheimer’s disease) are inherited genetically, through gene variants (sequences of a chemical code called DNA). The most common genetic variant that increases the risk of Alzheimer’s disease is called APOE4. Although we have known for over 25 years that inheriting an APOE4 genetic variant (also called an allele) increases Alzheimer’s disease risk, it is unclear how and why APOE4 increases this risk. Recent data has raised the possibility that APOE4 may act by increasing the activation of the complement pathway, a set of proteins that are used by immune cells to kill and eat bacteria, and that also play a role in “killing” and “eating” connections between nerve cells in the brain, known as synapses. In this project, we will examine whether people that carry the APOE4 allele (either 1 or 2 copies of this allele) have increased evidence of complement pathway activation in the fluid that bathes their brain and spinal cord, known as the cerebrospinal fluid (CSF) across the full adult lifespan. We have begun to assemble a set of CSF samples from our own studies as well as biobanks in the US and Europe. To date we have collected or received approval to use CSF samples from 400 individuals. This administrative supplement will allow us to recruit additional subjects between the ages of 18-39 to complete the set of CSF samples needed for this analysis. These samples will be analyzed using an advanced method that can measure the levels of a large percentage of all proteins present in human CSF, and which can precisely measure the levels of proteins in the complement pathway. Overall, this work will help us understand how and why APOE4 changes the function of the brain, and how and why it contributes to AD risk. This work is an early step towards identifying proteins or pathways that could be targeted by drugs to prevent Alzheimer’s disease in people that carry an APOE4 allele before the onset of any clinical symptoms.

痴呆症是一种常见的疾病，在老年人中频率增加。痴呆症是一种逐渐丧失思维和记忆技能，最终导致无法照顾自己和独立生活。导致美国老年人痴呆症的最常见原因是阿尔茨海默氏症，由多种生活方式/环境因素和遗传性的或家族性原因。许多家族特征(如患阿尔茨海默氏症的风险疾病)是通过基因变异(一种名为 DNA)。增加阿尔茨海默病风险的最常见的基因变异被称为载脂蛋白E4.尽管我们已经知道了超过25年的时间，遗传APOE4基因变异(也等位基因)增加阿尔茨海默病的风险，目前尚不清楚载脂蛋白4是如何以及为什么增加的这种风险。最近的数据增加了APOE4可能通过增加激活来起作用的可能性补体途径是免疫细胞用来杀死和吃掉细菌的一组蛋白质，这也在“杀死”和“吞食”大脑神经细胞之间的连接方面起到了作用，被称为突触。在这个项目中，我们将检查携带APOE4等位基因的人 (该等位基因的1个或2个副本)增加了补体途径激活的证据洗涤大脑和脊髓的液体，称为脑脊液(CSF)。成年后的全部寿命。我们已经开始从我们自己的研究中收集一套脑脊液样本以及美国和欧洲的生物库。到目前为止，我们已收集或获得批准使用400个人的脑脊液样本。这份行政副刊将允许我们招聘年龄在18-39岁之间的额外受试者，以完成所需的一套脑脊液样本这一分析。这些样本将使用一种先进的方法进行分析，该方法可以测量人类脑脊液中存在的大部分蛋白质的水平，并且可以精确地测量补体途径中的蛋白质水平。总体而言，这项工作将有助于我们了解载脂蛋白4如何和为什么改变大脑的功能，以及如何和为什么会增加AD的风险。这项工作是识别蛋白质或途径的早期步骤可能是药物的靶点，用于预防携带APOE4等位基因的人的阿尔茨海默病在出现任何临床症状之前。