Impact of apolipoprotein E isoforms on brain lipoproteins

载脂蛋白 E 亚型对脑脂蛋白的影响

基本信息

批准号：
10380849
负责人：
John Melchior
金额：
$ 19.41万
依托单位：
BATTELLE PACIFIC NORTHWEST LABORATORIES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380849
关键词：
Adopted Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology American Amino Acids Amyloid deposition Apolipoprotein A-I Apolipoprotein E Apolipoproteins Arginine Autopsy Biological Assay Blood Vessels Brain Cells Cerebral Amyloid Angiopathy Cerebrospinal Fluid Cerebrospinal Fluid Proteins Cerebrovascular Disorders Chemicals Clinical Complement Cryoelectron Microscopy Cysteine Development Disease Outcome Epidemic Etiology Exhibits Functional disorder Genotype Goals Health Heterogeneity High Density Lipoproteins Homeostasis Human Individual Isotopes Laboratories Lipid Binding Lipids Lipoprotein (a)Lipoproteins Low-Density Lipoproteins Measures Mediating Medical Metabolism Methods Modeling Molecular Molecular Conformation Molecular Sieve Chromatography Monitor Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Outcome Study Particle Size Persons Plasma Play Population Population Heterogeneity Protein Isoforms Proteins Proteome Proteomics Protocols documentation Regulation Reporting Resolution Risk Role Sampling Scaffolding Protein Senile Plaques Severities Shapes Sodium Chloride Structure Surface Techniques Technology Therapeutic Ultracentrifugation Variant Very low density lipoprotein Work analog base crosslink density design human subject improved lipid transport liquid chromatography mass spectrometry nanodisk particle protein complex reconstitution scaffold tool β-amyloid burden

项目摘要

Project Summary/Abstract Cerebrovascular dysfunction leads to the deposition of amyloid plaques and neurofibrillary tangles in the brain which underlie the development of Alzheimer’s disease (AD); an epidemic that affects more than five million Americans. Brain lipoproteins (BLps) are lipid-protein complexes that are essential for maintaining brain lipid homeostasis and protecting against neurodegeneration. Unfortunately, detailed studies on BLps have been severely limited as their abundance in cerebrospinal fluid (CSF) is 200-fold less than lipoprotein levels in plasma. It is known that BLps are produced independently in the central nervous system and they are thought to emulate compositional and functional features of plasma high-density lipoproteins (HDL). The dominant organizing scaffold on BLps is APOE which has three isoforms—APOE2, APOE3, and APOE4 that differ by cysteine- arginine exchanges at residues 112 and 158. Carriers of APOE4 are at an elevated risk for development and increased severity of AD. We hypothesize that, similar to APOA1 on HDL, APOE acts as a regulatory scaffold on BLps and conformational differences in APOE isoforms result in altered speciation and particle function that underlies the APOE isoform-specific impact on development of AD. We have developed a highly-sensitive lipoprotein profiling technology unique to our laboratory to overcome the BLp abundance hurdle in CSF. Our preliminary work shows that, like plasma HDL, BLps are a widely diverse population of unique particles with distinct protein complements. Moreover, we have developed a protocol for using cryo-electron microscopy to visualize lipid-bound apolipoproteins in unprecedented detail. We will leverage these technologies to 1) determine the impact of APOE isoform on the composition and distribution of BLps and 2) determine the molecular basis of how APOE isoforms structurally regulate BLps. Importantly, we will directly relate differences to clinical AD endpoints in the same individuals. This work will significantly accelerate our understanding of BLp composition, structure, and function and the specific role of APOE in the development of AD.

项目摘要/摘要脑血管功能障碍导致大脑中淀粉样斑块和神经原纤维缠结的沉积这是阿尔茨海默氏病（AD）发展的基础；影响超过500万的流行病美国人。脑脂蛋白（BLP）是脂质 - 蛋白质复合物，对于维持脑脂质至关重要稳态并防止神经变性。不幸的是，关于BLP的详细研究由于它们在脑脊液（CSF）中的丰度比血浆中的脂蛋白水平低200倍，因此受到严重限制。众所周知，BLP是在中枢神经系统中独立生产的，被认为是模仿的血浆高密度脂蛋白（HDL）的组成和功能特征。主导组织 Blps上的脚手架是ApoE，具有三种同工型-APOE2，APOE3和APOE4，与半胱氨酸不同残留112和158的精氨酸交换。APOE4载体的发育风险较高， AD的严重程度增加。我们假设，类似于HDL上的APOA1，APOE充当调节脚手架关于BLP和APOE同工型的构象差异导致规范和粒子功能改变基础是APOE同工型特定对AD发展的影响。我们已经开发了高度敏感的我们实验室独有的脂蛋白分析技术克服了CSF中的BLP抽象障碍。我们的初步工作表明，像等离子体HDL一样，BLP是一个广泛多样的独特颗粒，具有独特的蛋白质完成。此外，我们已经开发了一种用于使用冷冻电子显微镜的协议以前所未有的细节可视化脂质结合的载脂蛋白。我们将把这些技术利用为1）确定APOE同工型对BLPS组成和分布的影响，2）确定 APOE同工型在结构调节BLP的分子基础。重要的是，我们将直接相关的差异到同一个人的临床广告端点。这项工作将大大加速我们对BLP的理解 APOE在AD发展中的组成，结构和功能以及特定的作用。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human cerebrospinal fluid contains diverse lipoprotein subspecies enriched in proteins implicated in central nervous system health.

DOI：
10.1126/sciadv.adi5571
发表时间：
2023-09
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Merrill, Nathaniel J.;Davidson, W. Sean;He, Yi;Ludovico, Ivo Diaz;Sarkar, Snigdha;Berger, Madelyn R.;Mcdermott, Jason E.;Van Eldik, Linda J.;Wilcock, Donna M.;Monroe, Matthew E.;Kyle, Jennifer E.;Bruce, Kimberley D.;Heinecke, Jay W.;Vaisar, Tomas;Raber, Jacob;Quinn, Joseph F.;Melchior, John T.
通讯作者：
Melchior, John T.