Role of LR11 Ectodomain Ligands in the Regulation of APP Processing

LR11 胞外域配体在 APP 加工调节中的作用

• 批准号: 7500804
• 负责人: KRISTEN L SAGER
• 金额: $ 2.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500804
• 关键词: Address; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Binding; Brain; Brain region; Cell Culture System; Cell membrane; Cell surface; Cells; Cleaved cell; Endosomes; Enzyme-Linked Immunosorbent Assay; Enzymes; Genetic Risk; Genotype; Head; In Vitro; Ligand Binding; Ligand Binding Domain; Ligands; Light; Low Density Lipoprotein Receptor; Mediating; Methods; Molecular Chaperones; Monitor; Neurons; Peptides; Play; Process; Protein Isoforms; Proteins; Reaction; Recombinants; Regulation; Reporting; Role; Specificity; Staging; Techniques; Testing; Therapeutic; Work; amyloid precursor protein processing; apolipoprotein E-3; apolipoprotein E-4; base; head activator peptide; immunocytochemistry; inhibitor/antagonist; overexpression; protein transport; receptor; research study; response; secretase; trafficking

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.

描述（由申请人提供）：虽然在健康的大脑中LR11表达稳健，但这种低密度脂蛋白受体的表达在阿尔茨海默氏病（AD）脑中大大降低。此外，已知LR11在维持低水平的β-淀粉样蛋白（A3）中发挥作用，该肽被广泛认为在AD致病性级联反应中起关键作用。最近的证据表明，LR11通过调节淀粉样蛋白前体蛋白（APP）的细胞内定位来做到这一点，该蛋白（APP）从中产生了AP。 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基本的细胞培养系统表征了两个已知的LR11配体对APP的运输和处理的影响，并描绘了LR11在介导这些反应中的作用。将研究LR11如何介导这些效果，重点是在特定AIM 2中进行的APP的变化。在AIM 2A中，我们将重点介绍APOE3和E4如何指导LR11和APP的贩运，以及这些变化如何影响应用程序的处理。在AIM 2B中，我们将研究APOE2与LR11对应用程序运输和处理的影响与响应APOE4中的APP运输和处理的影响以及这些差异的基础机制不同。这些研究将更好地理解LR11在AD致病性级联反应中的作用，尤其是它调节大脑中应用程序的能力。最终，这项工作将开始奠定我们认为有一天会产生基于LR11的AD Therapeutics的基础工作。