权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Therapeutic potential-LXR ligands in Alzheimer's Disease

LXR配体在阿尔茨海默病中的治疗潜力

基本信息

批准号：
6942235
负责人：
ILIYA LEFTEROV
金额：
$ 5.71万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2006-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6942235
关键词：
Alzheimer&apos s disease amyloid proteins disease /disorder model gene induction /repression genetic transcription genetically modified animals laboratory mouse ligands membrane transport proteins nervous system disorder chemotherapy neurons nonhuman therapy evaluation retinoid binding proteins

项目摘要

DESCRIPTION (provided by applicant): This application is a resubmission in response to PAR-03-056 and particularly to Research topic 3. Druq Discovery for Coqnitive Decline and Alzheimer's Disease. Cholesterol (CL) is considered one of the main players in the pathogenesis of Alzheimer's disease (AD). It has been shown that accumulation of excess CL in hippocampal neurons increased Abeta production. Furthermore, prevalence of AD is reduced among people taking statins - CL lowering drugs. In contrast, plasma levels of HDL-cholesterol (HDL-CL) are inversely associated with risk of cardiovascular disease and AD. Understanding the mechanisms through which CL homeostasis affects APP processing and amyloid deposition will provide clues for better understanding the risk factors, prevention and treatment of AD. Liver X receptors (LXRalpha and beta) act as molecular sensors of cholesterol levels and respond by inducing processes that reduce cholesterol levels. The ABCA1 transporter which is under the transcriptional control of LXRs, mediates CL efflux and secretion of excess CL from cells to lipid-flee Apo-lipoproteins. It is considered a major determinant of plasma HDL concentration. We found that LXR/RXR agonists treatment of primary neurons increased ABCA1 expression and CL effiux to apolipoproteins A-I and E3, consequently decreasing CL content in these cells. More importantly, we demonstrated that these ligands alone or in combination with apolipoprotein A-I caused a substantial reduction in the stability of APP Cterminal fragments and decreased Abeta production. We hypothesize that transcriptional upregulation of ABCA1 triggered by pharmacological activation of LXR will affect the amyloidogenic processing of APP, with a decreased Abeta secretion and ultimately decreased amyloid deposition in the brain of AD model animals. To test our hypothesis we propose: Aim 1. To examine the role of LXR ligands and apolipoprotein-mediated cholesterol efllux on APP intracellular transport and Abeta generation. In cells stably expressing APPsw we will determine if LXR ligand treatment with or without apolipoproteins affects APP and BACE 1 vesicular transport from Golgi to plasma membrane and their endocytosis. To determine if the effect of LXR in neurons requires transcriptional upregulation of endogenous ABCA1, we will apply the same LXR ligand treatments in primary neuronal cultures derived from ABCA1wt and ABCA1-/- mice. Aim 2. To determine the effect of LXR synthetic pharmacological ligands on Aa generation and amyloid deposition in APP transgenic mice. By using APP23 mice we will test the critical question whether in-vivo administration of synthetic LXR agonists T0901317 and Hypocholamide, and the transcriptional activation of ABCA1 modulates Aa generation/secretion or the amount of Abeta deposits in the brain of AD transgenic model. The results of our study will advance the understanding how genes and proteins controlling intracellular CL content and its redistribution in the brain influence hAPP processing and Abeta deposition. We believe that the pharmacological manipulation of these regulatory mechanisms will validate LXRs as a valuable molecular target in the drug development and discovery of new therapeutic agents for prevention or treatment of Alzheimer's disease.

描述（由申请人提供）：本申请是针对PAR-03-056，特别是研究主题3的重新提交。Druq发现Coqlidine下降和阿尔茨海默病。胆固醇（CL）被认为是阿尔茨海默病（AD）发病机制的主要参与者之一。已经表明，海马神经元中过量CL的积累增加了Abeta的产生。此外，AD的患病率在服用他汀类- CL降低药物的人群中降低。相比之下，血浆高密度脂蛋白胆固醇（HDL-CL）水平与心血管疾病和AD的风险呈负相关。了解CL稳态影响APP加工和淀粉样蛋白沉积的机制将为更好地了解AD的危险因素、预防和治疗提供线索。肝脏X受体（LXR α和β）作为胆固醇水平的分子传感器，并通过诱导降低胆固醇水平的过程作出反应。ABCA 1转运蛋白在LXR的转录控制下，介导CL流出和过量CL从细胞分泌至脂质逃逸的载脂蛋白。它被认为是血浆HDL浓度的主要决定因素。我们发现，LXR/RXR激动剂处理的原代神经元增加ABCA 1的表达和CL对载脂蛋白A-I和E3的作用，从而降低这些细胞中的CL含量。更重要的是，我们证明了这些配体单独或与载脂蛋白A-I联合使用可导致APP C末端片段的稳定性显著降低，并减少A β的产生。我们假设，由LXR的药理学激活触发的ABCA 1的转录上调将影响APP的淀粉样蛋白形成加工，从而降低A β分泌并最终降低AD模型动物脑中的淀粉样蛋白沉积。为了验证我们的假设，我们提出：目标1.研究LXR配体和载脂蛋白介导的胆固醇流出对APP细胞内转运和Abeta生成的作用。在稳定表达APPsw的细胞中，我们将确定LXR配体与或不与载脂蛋白一起处理是否影响APP和BACE 1从高尔基体到质膜的囊泡转运及其内吞作用。为了确定LXR在神经元中的作用是否需要内源性ABCA 1的转录上调，我们将在源自ABCA 1 wt和ABCA 1-/-小鼠的原代神经元培养物中应用相同的LXR配体处理。目标二。确定LXR合成药理学配体对APP转基因小鼠中Aa生成和淀粉样蛋白沉积的影响。通过使用APP 23小鼠，我们将测试关键问题，即体内施用合成的LXR激动剂T0901317和Hypocholamide以及ABCA 1的转录激活是否调节AD转基因模型的脑中Aa产生/分泌或Abeta沉积的量。我们的研究结果将促进了解基因和蛋白质控制细胞内CL含量及其在大脑中的再分布如何影响hAPP加工和Abeta沉积。我们相信，这些调节机制的药理学操作将验证LXR作为一个有价值的分子靶点，在药物开发和发现新的治疗剂，用于预防或治疗阿尔茨海默氏病。