ApOE effects on neuron signaling and function via ApoER2

描述（由申请人提供）：APOE是阿尔茨海默病最强的遗传危险因素，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，我们已经定义了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，我们将重点关注最有趣的突触载脂蛋白e受体之一ApoER2及其作为突触信号分子的功能机制。此外，我们正在研究三种人类apoE亚型与ApoER2相互作用的差异，使用apoE靶向替代小鼠。该项目是两个地点的两位研究者之间的合作，利用ApoER2信号和多种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研究结果的相关性，并设计体外实验来确定体内研究结果的机制。有四个具体目标；前三组通过ApoER2研究apoE亚型的神经元信号功能；最后一个检查这些功能如何可能有助于神经变性的致病过程。1. 我们将确定三种人类载脂蛋白e亚型对神经元结构和突触功能的体内影响；2. 我们将在体外确定ApoER2对神经元信号传导的作用机制；3. 我们将定义ApoER2如何在体内影响神经元信号传导；和4。我们将把这些基本发现转化为两种方法来保护阿尔茨海默病病理改变模型中的突触丧失。这些相互联系和互补的目标将使我们能够确定apoE亚型在正常神经元功能中的重要作用，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导中的新功能，确定了这些受体改变突触功能的机制。他们还探讨了受体聚集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，将有关JNK激活和ApoER2受体聚集的初步发现转化为预防与神经变性相关的突触功能障碍的方法。

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.