Role of apoE structure and metabolism in neurodegeneration

apoE结构和代谢在神经退行性变中的作用

基本信息

批准号：
8235856
负责人：
ROBERT W. MAHLEY
金额：
$ 37.26万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235856
关键词：
Affect Age Aging Alzheimer&apos s Disease Antibodies Apolipoprotein E Apolipoproteins Area Astrocytes Behavior Binding Biochemical Pathway Blood - brain barrier anatomy Brain Cells Cerebrospinal Fluid Cholesterol Cholesterol Homeostasis Cognitive deficits Complex Craniocerebral Trauma Crystallography Data Degradation Pathway Electron Spin Resonance Spectroscopy Endoplasmic Reticulum Event Functional disorder Gene Targeting Goals Health Human Impaired cognition Indiana Ischemia Knock-in Mouse Link Lipid Binding Lipids Lipoproteins Low Density Lipoprotein Receptor Maintenance Mass Spectrum Analysis Mediating Metabolism Microglia Modeling Molecular Mus Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Oxidative Stress Pathway interactions Phospholipids Physiologic pulse Plasma Play Process Production Property Protein Conformation Protein Isoforms Proteins Proteolysis Proteomics Quality Control Relative (related person)Research Personnel Resolution Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role Shelter facility Staging Stress Structure System Testing Therapeutic Therapeutic Intervention Toxic effect Wild Type Mouse apolipoprotein E-3 apolipoprotein E-4 base biological adaptation to stress design endoplasmic reticulum stress genetic risk factor high risk improved inhibitor/antagonist insight lipid metabolism lipid transport mouse model neurotoxic novel novel therapeutic intervention particle protein expression protein folding repaired response stressor synaptogenesis therapeutic target two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Apolipoprotein (apo) E plays a key role in lipid metabolism and transport in plasma and the central nervous system. One of the three major human apoE isoforms, apoE4, is a major risk factor for Alzheimer's disease by as yet undefined mechanisms. Our long-range objective is to employ a structure-function approach to establish these mechanisms with the goal of identifying potential therapeutic interventions. This proposal focuses on two major areas related to this goal. First, we will extend the resolution of our x-ray diffraction and small-angle x- ray scattering model of apoE4 bound to phospholipids and compare the structures of apoE4 and apoE3 bound to lipid. Secondly, we will continue our studies in which we link the apoE4 structural property of domain interaction to neurodegeneration and functional and cognitive deficits. The brains of human apoE isoform knock in mice and our Arg-61 apoE mouse model in which domain interaction was introduced, contain lower levels of apoE4 and Arg-61 mouse apoE compared to apoE3 and mouse wild-type apoE, respectively. The lower levels were due to decreased secretion by astrocytes, in which the Arg-61 apoE was selectively degraded, inducing an unfolded protein stress response. Based on these studies, we hypothesize that domain interaction contributes to neurodegeneration through two effects on astrocytes. 1) Domain interaction is recognized as an abnormally folded protein, resulting in an endoplasmic reticulum stress response that leads to downstream effects on key biochemical pathways supporting neuronal integrity. 2) Decreased secretion of apoE4 results in lower levels of cholesterol to support synapse formation and neuronal maintenance. This hypothesis represents a novel paradigm in which apoE4 domain interaction contributes to neurodegeneration and functional and cognitive deficits, involving astrocytes in the absence of additional stressors. We believe that these effects are early events in apoE4 carriers and set the stage for more dramatic responses with the addition of brain stressors (e.g. age, ischemia or A2 toxicity). This paradigm links apoE structure with neurodegeneration and functional consequences and suggests that interference with domain interaction is a viable therapeutic approach. These studies hold the potential to determine the mechanisms by which apoE4 is associated with a high risk for Alzheimer's disease and other forms of neurodegeneration and for identifying therapeutic approaches to reduce this risk. PUBLIC HEALTH RELEVANCE: Apolipoprotein E4 (apoE4) a brain protein, is the major genetic risk factor for Alzheimer's disease although the basis for this association is unknown. Based on our apoE4 structure studies, we propose a new mechanism for this association involving astrocytes, which are cells in the brain that support and maintain nerve cells. These studies hold the potential to identify new therapeutic approaches to reverse the effects of apoE4 on Alzheimer's disease.

描述（由申请人提供）：载脂蛋白（apo）E在血浆和中枢神经系统中的脂质代谢和转运中发挥关键作用。 apoE4 是人类三种主要 apoE 同工型之一，它是阿尔茨海默病的主要危险因素，其机制尚未明确。我们的长期目标是采用结构功能方法来建立这些机制，以期确定潜在的治疗干预措施。该提案重点关注与此目标相关的两个主要领域。首先，我们将扩展与磷脂结合的apoE4的X射线衍射和小角X射线散射模型的分辨率，并比较与脂质结合的apoE4和apoE3的结构。其次，我们将继续研究，将 apoE4 结构域相互作用的结构特性与神经退行性变以及功能和认知缺陷联系起来。与 apoE3 和小鼠野生型 apoE 相比，人类 apoE 异构体敲入小鼠的大脑和引入结构域相互作用的 Arg-61 apoE 小鼠模型的 apoE4 和 Arg-61 小鼠 apoE 水平分别较低。较低水平是由于星形胶质细胞分泌减少，其中 Arg-61 apoE 被选择性降解，诱导未折叠的蛋白质应激反应。基于这些研究，我们假设域相互作用通过对星形胶质细胞的两种影响导致神经变性。 1) 结构域相互作用被认为是一种异常折叠的蛋白质，导致内质网应激反应，从而对支持神经元完整性的关键生化途径产生下游影响。 2) apoE4 分泌减少导致胆固醇水平降低，以支持突触形成和神经元维持。这一假说代表了一种新的范例，其中 apoE4 结构域相互作用会导致神经变性以及功能和认知缺陷，在没有额外压力源的情况下涉及星形胶质细胞。我们认为，这些影响是 apoE4 携带者的早期事件，并为加上脑应激源（例如年龄、缺血或 A2 毒性）后发生更剧烈的反应奠定了基础。这种范例将 apoE 结构与神经退行性变和功能后果联系起来，并表明干扰结构域相互作用是一种可行的治疗方法。这些研究有可能确定 apoE4 与阿尔茨海默病和其他形式的神经退行性疾病高风险相关的机制，并确定降低这种风险的治疗方法。公共健康相关性：载脂蛋白 E4 (apoE4) 是一种脑蛋白，是阿尔茨海默病的主要遗传风险因素，尽管这种关联的基础尚不清楚。基于我们的 apoE4 结构研究，我们提出了一种涉及星形胶质细胞的这种关联的新机制，星形胶质细胞是大脑中支持和维持神经细胞的细胞。这些研究有可能找到新的治疗方法来逆转 apoE4 对阿尔茨海默病的影响。