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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：
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.

项目总结/摘要痴呆症是一种常见的疾病，在老年人中发生频率增加。痴呆症是一种渐进性的思维和记忆能力，最终导致无法照顾自己和独立生活。老年痴呆症最常见的原因是老年痴呆症，多种生活方式/环境因素和遗传或家族原因。许多家族特征（如风险阿尔茨海默氏病的发展是遗传的，通过基因变异（一种化学物质的序列称为DNA）。最常见的遗传变异，增加老年人患阿尔茨海默病的风险，成年人（即60岁以上）称为APOE 4。虽然我们已经知道超过25年，继承一个 APOE 4遗传变异（也称为等位基因）增加阿尔茨海默病风险，目前尚不清楚如何以及为什么 APOE 4增加了这种风险。最近的数据表明，APOE 4可能通过增加细胞内的激活补体途径，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，突触在这个项目中，我们将检查携带APOE 4等位基因（1或2个拷贝）的人是否具有这种等位基因）在浸泡他们大脑的液体中具有增加的补体途径激活的证据，脊髓，称为脑脊液（CSF）。我们还将确定脑脊液补体 APOE 4等位基因携带者的通路激活与长期认知能力下降相关， 7.5年期间。最后，我们将确定是否在体内用一种肽来调节APOE生物学，抗病APOE 2等位基因这项工作将使用一种先进的方法进行，存在于人CSF中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，这项工作将帮助我们了解APOE 4如何以及为什么改变大脑的功能，以及它如何以及为什么会导致AD风险。这项工作是早期的一步寻找能够被药物靶向以预防阿尔茨海默病的蛋白质或途径，携带APOE 4等位基因的人