ApoE Receptor Biology and Neurodegeneration

描述（由申请人提供）：阿尔茨海默病（AD）最重要的遗传风险因素是载脂蛋白E基因。APOE编码载脂蛋白E（apoE）蛋白，其是中枢神经系统（CNS）中的主要载脂蛋白。ApoE与低密度脂蛋白受体家族相互作用，这些apoE受体由神经元和神经胶质表达。因此，apoE受体调节apoE代谢并介导apoE对神经元信号传导、APP加工、神经毒性和突触功能的影响。该计划的目标是利用五位科学家的重叠兴趣和不同的专业知识，研究CNS中apoE和apoE受体的生物学。本项目的目的是确定apoE受体在中枢神经系统中的表达和功能，以及它们的功能如何受到三种apoE亚型和细胞蛋白水解事件的调节。这些项目还包括可溶性受体的产生和功能的检查。在项目1中，LaDu博士将研究apoE受体和β-淀粉样肽如何介导3种人类apoE亚型的代谢。在项目2中，Estus博士将测试apoE受体基因内的遗传变异是否会改变其功能，并确定这些变异是否会影响AD的风险。在项目3中，Bu博士将定义影响这些受体之一LRP的运输和加工的因素，并确定LRP如何影响淀粉样前体蛋白。在项目4中，Dr. Werk将研究另一种大脑apoE受体ApoER 2，并确定其加工过程是如何调节的，并确定可溶性apoE受体的命运。在项目5中，Weeber博士将确定突触可塑性的apoE依赖性调节机制以及apoE受体激活对神经行为和神经可塑性的体内影响。 核心内容包括：A.行政核心（财务管理，保持五个研究中心之间的良好沟通，并监督apoE和apoE受体的年度研讨会）; B）分子细胞生物学核心（用于进行apoE、apoE受体和Abeta的标准化测定，用于开发、表征和分发新的通用试剂，以及用于生成新的转基因小鼠模型，作为本计划的一部分）;和C）转基因核心（所有小鼠都维持在Taconic，用于分发AD的转基因小鼠模型和具有改变的apoE受体水平的小鼠）。因此，该计划将提供有关apoE和apoE受体如何影响阿尔茨海默病发病机制的新的和有价值的信息。

DESCRIPTION (as provided by applicant): The most important genetic risk factor for Alzheimer's disease (AD) is the APOE gene. APOE encodes the apolipoprotein E (apoE) protein, the main apolipoprotein in the central nervous system (CNS). ApoE interacts with the family of low density lipoprotein receptors, and these apoE receptors are expressed by neurons and glia. Thus, apoE receptors regulate apoE metabolism and mediate the effects of apoE on neuronal signaling, APP processing, neurotoxicity, and synaptic function. The goal of this Program is to take advantage of the overlapping interests and diverse expertise of five scientists examining the biology of apoE and apoE receptors in the CNS. The Aims of this Program are to define the expression and function of apoE receptors in the CNS, and how their functions are regulated by the three apoE isoforms and cellular proteolytic events. These projects also include an examination of the generation and function of soluble receptors. In Project 1, Dr. LaDu will examine how apoE receptors and beta-amyloid peptide mediate the metabolism of the 3 human apoE isoforms. In Project 2, Dr. Estus will test whether genetic variations within apoE receptor genes alter their functions and define whether these variations affect the risk of AD. In Project 3, Dr. Bu will define factors that affect the trafficking and processing of one of these receptors, LRP, and determine how LRP affects the amyloid precursor protein. In Project 4, Dr. Rebeck will examine another brain apoE receptor, ApoER2, and determine how its processing is regulated, and define the fate of soluble apoE receptors. In Project 5, Dr. Weeber will determine the mechanisms of apoE-dependent modulation of synaptic plasticity and in vivo effects of apoE receptor activation on neurobehavior and neuroplasticity. THE CORES INCLUDE: A) Administrative Core (for fiscal management, maintaining good communications between the five sites and overseeing a yearly symposium on apoE and apoE receptors); B) Molecular Cell Biology Core (for conducting standardized assays of apoE, apoE receptors, and Abeta, for developing, characterizing and distributing new common reagents, and for generating new transgenic mouse models as part of this Program); and C) Transgenic Core (all mice are maintained at Taconic, for distributing transgenic mouse models of AD and mice with altered levels of apoE receptors). This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease.