ApOE effects on neuron signaling and function via ApoER2

ApOE 通过 ApoER2 对神经元信号传导和功能产生影响

• 批准号: 8135051
• 负责人: G WILLIAM REBECK
• 金额: $ 50.78万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135051
• 关键词: Adaptor Signaling Protein; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid deposition; Animal Behavior; Animals; Apolipoprotein E; Behavior; Biochemistry; Biological Assay; Brain; Calcium; Cell membrane; Cellular biology; Collaborations; Cytoplasmic Tail; DLG4 gene; Data; Dendritic Spines; Disease; Electrophysiology (science); Evaluation; Experimental Designs; Fluorescence; Functional disorder; Genotype; Golgi Apparatus; Hippocampus (Brain); Homeostasis; Human; In Vitro; Individual; Inflammation; Knockout Mice; LDL-Receptor Related Protein 1; Learning; MAPK8 gene; Mediating; Memory; Memory Loss; Methodology; Modeling; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurons; Phosphorylation; Physiology; Predisposition; Principal Investigator; Process; Protein Isoforms; Proteins; Publishing; RNA Splicing; Receptor Activation; Receptor Signaling; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Signaling Molecule; Site; Slice; Staining method; Stains; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic; Translating; Vertebral column; Work; aged; apolipoprotein E receptor 2; base; computerized data processing; design; genetic risk factor; in vivo; inhibitor/antagonist; interest; mouse model; neurobehavioral; prevent; programs; promoter; public health relevance; receptor; research study; response; synaptic function; synaptogenesis; tau phosphorylation; translational approach

DESCRIPTION (provided by applicant): APOE is the strongest genetic risk factor for Alzheimer's disease and many of its actions in the brain are mediated by specific apoE receptors. Over the past several years, we have defined various signaling roles for apoE and apoE receptors in the brain, and examined how they affect neuronal physiology and animal behavior. In this proposal, we are focusing on one of the most interesting synaptic apoE receptors, ApoER2, and its mechanism of function as a synaptic signaling molecule. Furthermore, we are addressing how the three human apoE isoforms differ in their interactions with ApoER2, using APOE targeted replacement mice. This project is a collaboration between two investigators at two sites, to make use of common interests in ApoER2 signaling and diverse experimental techniques. By conducting both in vitro and in vivo experiments, we will be able to test the in vivo relevance to in vitro findings and design in vitro experiments to define mechanisms for in vivo findings. There are four specific aims; the first three examine the neuronal signaling functions of apoE isoforms via ApoER2; the last one examines how those functions may contribute to pathogenic processes of neurodegeneration. 1. We will determine the in vivo effects of the three human apoE isoforms on neuronal structure and synaptic function; 2. We will define mechanisms of ApoER2 effects on neuronal signaling in vitro; 3. We will define how ApoER2 affects neuronal signaling in vivo; and 4. We will translate these basic findings into two approaches to protecting against synaptic loss in models with Alzheimer's disease pathological changes. These connected and complementary aims will allow us to define important roles of apoE isoforms in normal neuronal function, which may contribute to the associated risk of AD. These experiments also address new functions of apoE receptors in neuronal signaling, defining mechanisms by which these receptors alter synaptic function. They also explore the role of receptor clustering in normal receptor signaling mechanisms. Finally, they will test two important hypotheses about how APOE genotype alters the risk of Alzheimer's disease, translating preliminary findings about JNK activation and ApoER2 receptor clustering into approaches to prevent the synaptic dysfunction associated with neurodegeneration. PUBLIC HEALTH RELEVANCE: Alzheimer's disease affects over 5 million people in the USA already, and the numbers will triple in 40 years giving the increasing numbers of aged citizens. APOE is the strongest genetic risk factor for Alzheimer's disease, influencing over half of all cases, but we do not know how it influences the disease. This proposed research will address the actions of apoE in the brain, and identify ways that it could be affecting Alzheimer's disease.

描述(申请人提供)：载脂蛋白E是阿尔茨海默病最强的遗传风险因素，它在大脑中的许多作用是由特定的载脂蛋白E受体介导的。在过去的几年里，我们已经定义了脑中apoE和apoE受体的各种信号作用，并研究了它们如何影响神经生理学和动物行为。在这个提案中，我们将重点关注最有趣的突触载脂蛋白E受体之一，ApoER2，以及它作为突触信号分子的作用机制。此外，我们正在使用APOE靶向替换小鼠来研究三种人类apoE亚型在与ApoER2相互作用方面的不同之处。这个项目是两个地点的两名研究人员之间的合作，以利用对ApoER2信号和不同实验技术的共同兴趣。通过进行体外和体内实验，我们将能够测试体内与体外发现的相关性，并设计体外实验以确定体内发现的机制。有四个具体的目标；前三个目标是通过ApoER2研究apoE亚型的神经元信号功能；最后一个目标是研究这些功能如何参与神经退行性变的发病过程。1.我们将确定三种人类apoE亚型在体内对神经元结构和突触功能的影响；2.我们将在体外确定ApoER2对神经元信号转导的作用机制；3.我们将定义ApoER2在体内如何影响神经元信号转导；以及4.我们将把这些基本发现转化为两种方法，以防止阿尔茨海默病病理变化模型中突触丢失的发生。这些相互联系和互补的目标将使我们能够确定apoE亚型在正常神经功能中的重要作用，这可能有助于AD的相关风险。这些实验还探讨了载脂蛋白E受体在神经元信号传递中的新功能，确定了这些受体改变突触功能的机制。他们还探索了受体聚集在正常受体信号机制中的作用。最后，他们将测试两个关于APOE基因如何改变阿尔茨海默病风险的重要假设，将关于JNK激活和ApoER2受体聚集的初步发现转化为预防与神经退化相关的突触功能障碍的方法。 与公共卫生相关：阿尔茨海默病在美国已经影响了500多万人，随着老年公民数量的增加，这一数字将在40年内增加两倍。载脂蛋白E是阿尔茨海默病最强的遗传风险因素，影响了超过一半的病例，但我们不知道它是如何影响疾病的。这项拟议的研究将解决载脂蛋白E在大脑中的作用，并确定它可能影响阿尔茨海默病的方式。