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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，在老年人中发生频率增加。痴呆是一逐渐丧失思维和记忆能力，最终导致无法照顾自己，独立生活。美国老年痴呆症最常见的原因是阿尔茨海默病，由于多种生活方式/环境因素而发展，遗传或家族原因。许多家族特征（如患老年痴呆症的风险疾病）是遗传的，通过基因变异（化学密码序列，称为 DNA）。最常见的增加阿尔茨海默病风险的遗传变异被称为 APOE 4.虽然我们已经知道超过25年，遗传APOE4遗传变异（也称为等位基因）增加阿尔茨海默病的风险，目前还不清楚APOE4如何以及为什么增加这个风险。最近的数据表明，APOE 4可能通过增加细胞的活化来发挥作用。补体途径是一组被免疫细胞用来杀死和吃掉细菌的蛋白质，并且在"杀死"和"吃掉"大脑中神经细胞之间的连接中也起着作用，称为突触。在这个项目中，我们将检查携带APOE4等位基因的人是否（该等位基因的1个或2个拷贝）的补体途径激活的证据增加，脑脊髓液（CSF）是一种浸泡大脑和脊髓的液体，成年人的全部寿命。我们已经开始收集一组我们自己研究的脑脊液样本以及美国和欧洲的生物银行。到目前为止，我们已经收集或获得批准，使用来自400个人的CSF样本。这份行政补助将使我们能够招募年龄在18 - 39岁之间的额外受试者，以完成所需的CSF样本集，这个分析。这些样本将使用先进的方法进行分析，人CSF中存在的所有蛋白质的大百分比的水平，并且其可以精确地测量补体途径中的蛋白质水平。总的来说，这项工作将有助于我们了解APOE4如何以及为什么改变大脑的功能，以及它如何以及为什么改变大脑的功能。增加AD风险。这项工作是识别蛋白质或途径的早期步骤，可以被药物靶向预防携带APOE4等位基因的人患阿尔茨海默病在任何临床症状出现之前