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

基本信息

批准号：
8312020
负责人：
G WILLIAM REBECK
金额：
$ 5.77万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/8312020
关键词：
Adaptor Signaling Protein Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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（由申请人提供）：APOE 是阿尔茨海默氏病最强的遗传风险因素，其在大脑中的许多作用是由特定的 apoE 受体介导的。在过去的几年里，我们定义了 apoE 和 apoE 受体在大脑中的各种信号作用，并研究了它们如何影响神经元生理和动物行为。在本提案中，我们重点关注最有趣的突触 apoE 受体之一 ApoER2 及其作为突触信号分子的功能机制。此外，我们正在使用 APOE 靶向替代小鼠来研究三种人类 apoE 亚型与 ApoER2 相互作用的不同之处。该项目是两个地点的两名研究人员之间的合作，旨在利用对 ApoER2 信号传导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，并设计体外实验来定义体内发现的机制。有四个具体目标；前三个通过 ApoER2 检查 apoE 亚型的神经信号传导功能；最后一项研究了这些功能如何促进神经退行性病变的致病过程。 1. 我们将确定三种人类apoE亚型对神经元结构和突触功能的体内影响； 2. 我们将在体外定义ApoER2对神经元信号传导的影响机制； 3. 我们将定义ApoER2如何影响体内神经元信号传导； 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的突触损失。这些相互关联且互补的目标将使我们能够定义 apoE 亚型在正常神经元功能中的重要作用，这可能会导致 AD 的相关风险。这些实验还解决了 apoE 受体在神经元信号传导中的新功能，定义了这些受体改变突触功能的机制。他们还探讨了受体簇在正常受体信号传导机制中的作用。最后，他们将测试关于 APOE 基因型如何改变阿尔茨海默病风险的两个重要假设，将 JNK 激活和 ApoER2 受体聚集的初步发现转化为预防与神经退行性变相关的突触功能障碍的方法。公共健康相关性：阿尔茨海默病已影响美国超过 500 万人，而且随着老龄化人口的不断增加，这一数字将在 40 年内增加两倍。 APOE 是阿尔茨海默病最强的遗传风险因素，影响了一半以上的病例，但我们不知道它如何影响这种疾病。这项拟议的研究将解决 apoE 在大脑中的作用，并确定它可能影响阿尔茨海默病的方式。