ABCA1: A Potential Therapeutic Target for AD

ABCA1：AD 的潜在治疗靶点

• 批准号: 7013586
• 负责人: RADOSVETA KOLDAMOVA
• 金额: $ 14.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013586
• 关键词: Alzheimer' s disease; aging; amyloid proteins; amyloidosis; brain disorder chemotherapy; cell line; cholesterol; drug design /synthesis /production; drug screening /evaluation; gene expression; gene induction /repression; genetic polymorphism; genetically modified animals; laboratory mouse; ligands; membrane transport proteins; neurons; nonhuman therapy evaluation; nuclear receptors; peroxisome proliferator activated receptor; pharmacology; phenotype; protein metabolism; stimulant /agonist; therapy design /development

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and atherosclerosis share common risk factors. Epidemiological and clinical studies have suggested that vascular risk factors might be important in both diseases. Notably, recent genetic data demonstrated that carders of a common genetic variant (R219K) of ATP-binding cassette transporter A1 (ABCA1), initially linked to a decreased severity of atherosclerosis, have delayed age at onset of Alzheimer's disease. ABCA1 is a major regulator of cholesterol homeostasis. Mutations in the ABCA1 gene cause severe HDL deficiencies characterized by accumulation of cholesterol in cells and prevalent atherosclerosis. The transcriptional upregulation of ABCA1 is controlled by nuclear receptors LXR and PPARgamma - shown to increase HDL levels and decrease atherosclerotic lesions in vivo. Recently, others and we demonstrated that ligands for LXRs increased ABCA1 expression in neuronal cells and reduced amyloid beta (ABeta) secretion. Thus, transcriptional upregulation of ABCA1 triggered by pharmacological activation of LXRs and PPARgamma may decrease amyloid production and plaque formation in the brain. Our proposal has two principal objectives: Aim 1. To determine the effect of synthetic LXR and PPARgamma ligands on ABCA1 expression and APP processing in vitro. We will screen a number of synthetic LXR ligands and PPARgamma agonists for their inhibitory potential on ABeta production in vitro. The effect will be determined in a neuronal cell line and primary neurons. Aim 2. To validate ABCA1 as a therapeutic target by comparing AD-phenotype in APP23/ABCA1 wt and APP23/ABCA1-/- and by further treatments of these mice with LXR and PPARgamma ligands. This Aim has two main objectives: 1). To determine if the targeted disruption of ABCA1 influences APP23 phenotype in APP23/ABCA1-/- in comparison to APP23/ABCA1/wt mice, and 2). To examine ff LXR and PPARgamma ligands exert their effect on ABeta secretion/deposition through ABCAl-dependent mechanism. We will compare the effect of LXR and PPARgamma agonists on AD-like pathology in APP23 mice with either wild type or disrupted ABCA1 gene. We will use two age groups: younger animals to examine the effect exclusively on ABeta production and older mice to answer the question if treatment affects amyloid deposition. The results of our study will advance the understanding how the genes that control intracellular cholesterol content and its redistribution in the brain, influence APP processing and ABeta deposition. The possibility to upregulate ABCA1 by LXR/PPARgamma agonists will establish the pharmacological intervention aiming at ABCA1 as a valuable approach in the drug development and discovery of new therapeutic agents for prevention and/or slowing the progression of Alzheimer's disease.

描述（由申请人提供）：阿尔茨海默病（AD）和动脉粥样硬化有共同的危险因素。流行病学和临床研究表明，血管危险因素可能在这两种疾病中都很重要。值得注意的是，最近的遗传数据表明，ATP 结合盒转运蛋白 A1 (ABCA1) 的常见遗传变异 (R219K) 最初与动脉粥样硬化严重程度降低有关，可延迟阿尔茨海默病的发病年龄。 ABCA1 是胆固醇稳态的主要调节因子。 ABCA1 基因突变会导致严重的 HDL 缺乏，其特征是细胞内胆固醇积聚和普遍的动脉粥样硬化。 ABCA1 的转录上调是由核受体 LXR 和 PPARgamma 控制的 - 显示可增加体内 HDL 水平并减少动脉粥样硬化病变。最近，其他人和我们证明 LXR 的配体增加了神经元细胞中 ABCA1 的表达并减少了淀粉样蛋白 β (ABeta) 的分泌。因此，由 LXR 和 PPARgamma 的药理激活引发的 ABCA1 转录上调可能会减少大脑中淀粉样蛋白的产生和斑块的形成。我们的提案有两个主要目标： 目标 1. 确定合成 LXR 和 PPARgamma 配体对体外 ABCA1 表达和 APP 加工的影响。我们将筛选一些合成的 LXR 配体和 PPARgamma 激动剂，以确定它们对体外 Aβ 产生的抑制潜力。将在神经元细胞系和原代神经元中确定效果。目标 2. 通过比较 APP23/ABCA1 wt 和 APP23/ABCA1-/- 中的 AD 表型以及用 LXR 和 PPARgamma 配体进一步治疗这些小鼠，验证 ABCA1 作为治疗靶点。该目标有两个主要目标：1)。与 APP23/ABCA1/wt 小鼠相比，确定 ABCA1 的靶向破坏是否影响 APP23/ABCA1-/- 中的 APP23 表型，以及 2)。为了检查LXR和PPARγ配体通过ABCA1依赖性机制发挥其对ABeta分泌/沉积的影响。我们将比较 LXR 和 PPARgamma 激动剂对具有野生型或破坏的 ABCA1 基因的 APP23 小鼠的 AD 样病理学的影响。我们将使用两个年龄组：年轻的动物专门检查对 Aβ 产生的影响，而老年小鼠则回答治疗是否影响淀粉样蛋白沉积的问题。我们的研究结果将促进人们了解控制细胞内胆固醇含量及其在大脑中重新分布的基因如何影响 APP 处理和 Aβ 沉积。通过 LXR/PPARgamma 激动剂上调 ABCA1 的可能性将建立以 ABCA1 为目标的药理学干预，作为药物开发和发现用于预防和/或减缓阿尔茨海默氏病进展的新治疗剂的有价值的方法。