Role of LR11 Ectodomain Ligands in the Regulation of APP Processing

描述(申请人提供)：虽然LR11在健康大脑中的表达很强，但这种低密度脂蛋白受体在阿尔茨海默病(AD)大脑中的表达显著减少。此外，众所周知，LR11在维持低水平的β淀粉样蛋白(A3)方面发挥作用，这种多肽被广泛认为在AD致病级联中发挥关键作用。最近的证据表明，LR11是通过调节淀粉样前体蛋白(APP)的细胞内定位来实现这一点的，AP是由APP产生的。由于不同的APP加工酶在不同的亚细胞间被发现，改变在细胞中发现APP的位置最终决定了有多少APP被切割成A(3)。鉴于LR11的这一拟议的作用，我们假设通过受体胞外区域中已知的配体结合域与LR11相互作用的化合物能够影响LR11对AP的已知作用。在这项研究中，我们将使用一个基本的细胞培养系统来表征两个已知的LR11配体对APP运输和加工的影响，并描述LR11在介导这些反应中的作用。在特定的目标1中，我们将检验小肽头部激活剂(HA)影响LR11功能和调节APP处理的假设。在目标1A中，我们将确定HA与LR11结合对处理APP的影响，在目标1B中，我们将研究LR11如何调节这些影响，重点是APP的改变贩运。在特定的目标2中，我们将检验apoE影响LR11功能并以异构体依赖的方式调控APP转运的假设。在目标2A中，我们将重点研究apoE3和E4如何能够指导LR11和APP的贩运，以及这些变化如何影响APP的处理。在目标2B中，我们将研究APOE2与LR11结合对应用程序贩运和处理的影响与响应apoE4中看到的影响有何不同，以及这些差异背后的机制。这些研究将使我们更好地了解LR11在AD致病级联中的作用，特别是它调节大脑中APP的能力。最终，这项工作将开始奠定基础，我们相信有一天将产生基于LR11的AD疗法。

DESCRIPTION (provided by applicant): While LR11 expression is robust in the healthy brain, the expression of this low density lipoprotein receptor is drastically reduced in Alzheimer's disease (AD) brain. Moreover, LR11 is known to play a role in maintaining low levels of beta amyloid (A3), the peptide widely believed to play a critical role in the AD pathogenic cascade. Recent evidence has suggested that LR11 does this by regulating the the intracellular localization of the amyloid precursor protein (APP), which from which Ap is generated. Because different APP - processing enzymes are found in different sub-cellular compartments, altering where in the cell APP is found ultimately determines how much APP is cleaved into A(3. In light of this proposed role for LR11, we hypothesize that compounds that interact with LR11 through known ligand binding domains in the ectodomain of the receptor are capable of influencing the known effects of LR11 on Ap. In this study, we will use a basic cell culture system to characterize the effects of two known LR11 ligands on the trafficking and processing of APP, and to delineate the role of LR11 in mediating these reactions. In Specific Aim 1, we will test the hypothesis that the small peptide head activator (HA) influences LR11 function an modulates APP processing. In Aim 1 A, we will determine the effects of HA binding to LR11 on the processing APP and in Aim 1B, we will look at how LR11 mediates those effects, focusing on the altered trafficking of APP. In Specific Aim 2, we will test the hypothesis that apoE influences LR11 function and modulates the trafficking of APP in an isoform dependent manner. In Aim 2A, we will focus on how apoE3 and E4 are able to direct the trafficking of LR11 and APP, and how these changes influence the processing of APP. In Aim 2B, we will look at how the effects of apoE2 binding to LR11 on APP trafficking and processing differ from those seen in response apoE4 and the mechanisms underlying these differences. These studies will better our understanding of the role of LR11 in the AD pathogenic cascade and in particular, its ability to regulate APP in the brain. Ultimately, this work will begin to lay the ground work that we believe will someday yield LR11 based - AD therapeutics.