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APOE基因。APOE编码载脂蛋白E （APOE）蛋白，载脂蛋白E是中枢神经系统（CNS）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受体在神经元和胶质细胞中表达。因此，载脂蛋白e受体调节载脂蛋白e代谢，介导载脂蛋白e对神经元信号、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来研究载脂蛋白e和载脂蛋白e受体在中枢神经系统中的生物学。本项目的目的是确定载脂蛋白e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载脂蛋白e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博士将研究载脂蛋白e受体和β -淀粉样肽如何介导3种人类载脂蛋白e亚型的代谢。在项目2中，Estus博士将测试apoE受体基因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博士将定义影响其中一种受体LRP的运输和加工的因素，并确定LRP如何影响淀粉样蛋白前体蛋白。在Project 4中，Rebeck博士将研究另一种脑载脂蛋白e受体ApoER2，并确定其加工过程是如何被调节的，并确定可溶性载脂蛋白e受体的命运。在Project 5中，weber博士将确定apoE依赖性突触可塑性调节的机制，以及apoE受体激活对神经行为和神经可塑性的体内影响。

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.