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: 6811586
• 负责人: JAMES J LAH
• 金额: $ 30.98万
• 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/6811586
• 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)：越来越多的证据表明脂蛋白受体参与了常见的、零星的阿尔茨海默病(AD)病例。载脂蛋白E(ApoE)e4等位基因变异增加了AD的风险，apoE受体与B-淀粉样前体蛋白(APP)和β-淀粉样多肽(AB)的代谢有关，后者被认为在AD中发挥核心作用。利用基因芯片筛选AD患者基因表达的变化，我们发现LR11的表达发生了变化，LR11是一种多功能的载脂蛋白E受体，主要在大脑中表达。LR11以前没有与AD相关，但我们令人兴奋的初步发现显示，在AD的脆弱神经元中，LR11显著丢失。此外，LR11似乎与APP相互作用，我们发现LR11的表达与AB水平之间存在重要联系。这些观察为这一假设的中心假设提供了强有力的基础：多功能apoE受体LR11通过与B-淀粉样前体蛋白和AB肽的相互作用参与阿尔茨海默病的发病。在目标1中，我们将表征LR11与APP的分子相互作用，并生成将用于后续AIMS的修改后的LR11结构。 在目标2中，我们将检测LR11对APP亚细胞分布的影响，并评估其对APP蛋白降解过程的影响。在目标3中，补充研究将测试LR11调节AB产生和调节AB清除的能力。在目标4中，我们将产生并表征LR11水平降低的细胞培养和小鼠模型系统，以模拟在AD大脑中观察到的表达丢失。这些目的将检验我们的中心假设，这些发现将产生对载脂蛋白E受体生物学的见解，结果可能确定LR11为AD治疗的重要新靶点。