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：
10650372
负责人：
Miles Berger
金额：
$ 78.47万
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/10650372
关键词：
Adult Age Alleles Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk American Amyloid beta-Protein Apolipoprotein E Appearance Autopsy Bacteria Bathing Biological Assay Biological Markers Biology Brain Brain Injuries Caring Cells Cerebrospinal Fluid Chemicals Classical Complement Pathway Code Cognition Cognitive Complement Complement 1q Complement Activation Complement Inactivators DNA Data Dementia Deposition Development Disease Disease Resistance Drug Targeting Eating Elderly Encephalitis Enrollment Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Frequencies Gender Genetic Genetic Carriers Hereditary Disease Human Hybrids Immune Impaired cognition In Vitro Inherited Late Onset Alzheimer Disease Lead Life Life Style Liquid substance Longevity Measures Memory Methods Molecular Mus Neurites Neurofibrillary Tangles Neurons Operative Surgical Procedures Outcome Pathology Pathway interactions Patients Peripheral Persons Pharmaceutical Preparations Phase II Clinical Trials Postoperative Period Process Proteins Proteomics Regulation Risk Role Sampling Senile Plaques Set protein Signal Transduction Spinal Cord Spinal Puncture Synapses Testing Thinking Work abeta deposition apolipoprotein E-3 apolipoprotein E-4 cohort complement pathway genetic risk factor genetic variant in vivo insight mimetics nervous system disorder novel peptidomimetics postoperative delirium prevent protein function sex skills tau Proteins tau-1 trait

项目摘要

Project Summary/Abstract 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 in older adults (ie above age 60) 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). We will also determine whether CSF complement pathway activation in APOE4 allele carriers is associated with long term cognitive decline over a 7.5 year period. Finally, we will determine whether modulating APOE biology in vivo with a peptide that “mimics” the disease-resistant APOE2 allele. This work will be performed 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.

项目概要/摘要痴呆症是一种常见疾病，在老年人中发病率增加。痴呆症是一种渐进性丧失。思维和记忆能力最终导致无法照顾自己和独立生活。美国老年人痴呆症最常见的原因是阿尔茨海默氏病，该病是由于多种生活方式/环境因素以及遗传或家族原因（例如风险）。阿尔茨海默病的发病率是通过基因变异（化学物质的序列）遗传的。称为 DNA 的最常见的遗传变异，会增加老年人患阿尔茨海默病的风险。成人（即 60 岁以上）被称为 APOE4，尽管我们 25 年前就知道遗传性 AOE4。 APOE4 基因变异（也称为等位基因）会增加阿尔茨海默病的风险，目前尚不清楚如何以及为何 APOE4 增加了这种风险，最近的数据表明 APOE4 可能通过增加补体途径的激活，免疫细胞使用一组蛋白质来杀死和吃掉细菌，它还在“杀死”和“吃掉”大脑神经细胞之间的连接中发挥作用，称为在这个项目中，我们将检查是否携带 APOE4 等位基因（1 个或 2 个拷贝）的人。这个等位基因）增加了沐浴大脑的液体中补体途径激活的证据，脊髓，称为脑脊液 (CSF) 我们还将确定 CSF 是否补体。 APOE4 等位基因携带者的通路激活与长期认知能力下降有关最后，我们将确定是否用“模拟”的肽在体内调节 APOE 生物学。这项工作将使用一种可以测量的先进方法来进行。人类脑脊液中大部分蛋白质的水平，并且可以精确测量总体而言，这项工作将帮助我们了解 APOE4 的作用和原因。改变大脑的功能，以及它如何以及为何导致 AD 风险。这项工作是早期的一步。识别可作为预防阿尔茨海默氏病药物靶向的蛋白质或途径携带 APOE4 等位基因的人。