ApoE Receptor LR11 in Alzheimer's Etiopathogenesis

ApoE 受体 LR11 在阿尔茨海默病发病机制中的作用

• 批准号: 7110266
• 负责人: JAMES J LAH
• 金额: $ 30.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110266
• 关键词: Alzheimer' s disease; RNA interference; amyloid proteins; apolipoprotein E; enzyme linked immunosorbent assay; gene mutation; genetically modified animals; immunofluorescence technique; laboratory mouse; low density lipoprotein receptor; pathologic process; posttranslational modifications; protein localization; protein protein interaction; proteolysis; tissue /cell culture

DESCRIPTION (provided by applicant): Converging lines of evidence have highlighted the involvement of lipoprotein receptors in common, sporadic cases of Alzheimer's disease (AD). The apolipoprotein E (apoE) e4 allelic variant increases AD risk, and the apoE receptors have been linked to the metabolism of the B-amyloid precursor protein (APP) and beta-amyloid peptide (AB), which are believed to play a central role in AD. Using cDNA microarrays to screen changes in gene expression in AD patients, we discovered altered expression of LR11, a multifunctional apoE receptor that is expressed predominantly in brain. LR11 has not previously been linked to AD, but our exciting preliminary findings reveal marked loss of LR11 among vulnerable neurons in AD. In addition, LR11 appears to interact with APP, and we have found important links between LR11 expression and levels of AB These observations provide a strong foundation for the central hypothesis of this proposal: The multifunctional apoE receptor LR11 participates in Alzheimer's disease pathogenesis through its interactions with B-amyloid precursor protein and AB peptide. In Aim 1, we will characterize the molecular interactions of LR11 with APP and generate modified LR11 constructs that will be used in subsequent Aims. In Aim 2, we will examine the ability of LR11 to influence the subcellular distribution of APP and assess the effects on proteolytic processing of APP. In Aim 3, complementary studies will test the ability of LR11 to modulate AB production and mediate AB clearance. In Aim 4, we will generate and characterize cell culture and mouse model systems with reduced LR11 levels to mimic the loss of expression observed in AD brains. These Aims will test our central hypothesis and the findings will generate insights into the biology of apoE receptors, and the results may identify LR11 as an important new target for AD therapeutics.

描述（由申请人提供）：融合的证据线突显了脂蛋白受体参与常见的阿尔茨海默氏病（AD）的零星病例。载脂蛋白E（APOE）E4等位基因变体增加了AD风险，并且APOE受体与B-淀粉样蛋白前体蛋白（APP）和β-淀粉样蛋白肽（AB）的代谢有关，这些肽（AB）被认为在AD中起着中心作用。使用cDNA微阵列筛选AD患者基因表达的变化，我们发现LR11的表达改变，LR11是一种多功能的APOE受体，主要在大脑中表达。 LR11以前没有与AD联系在一起，但是我们令人兴奋的初步发现表明，AD中脆弱神经元中LR11的损失明显丧失。此外，LR11似乎与APP相互作用，我们发现LR11表达和AB水平之间的重要联系为该提案的中心假设奠定了坚实的基础：多功能APOE受体LR11通过与B-淀粉样蛋白前体蛋白和AB peptide的相互作用参与了阿尔茨海默氏病的发病机理。在AIM 1中，我们将表征LR11与APP的分子相互作用，并生成经过改进的LR11构建体，这些构建体将用于后续目标。 在AIM 2中，我们将研究LR11影响APP的亚细胞分布的能力，并评估对APP蛋白水解处理的影响。在AIM 3中，互补研究将测试LR11调节AB生产并介导AB清除率的能力。在AIM 4中，我们将生成并表征具有LR11水平降低的细胞培养和小鼠模型系统，以模仿AD大脑中观察到的表达丧失。这些目标将检验我们的中心假设，发现将对APOE受体的生物学产生见解，结​​果可能会将LR11识别为AD疗法的重要新靶标。