ABCA1: A Potential Therapeutic Target for AD

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风险因素。流行病学和临床研究表明，血管危险因素可能是重要的，在这两种疾病。值得注意的是，最近的遗传数据表明，ATP结合盒转运蛋白A1（ABCA 1）的一种常见遗传变异（R219 K）的携带者，最初与动脉粥样硬化的严重程度降低有关，在阿尔茨海默病发病时延迟了年龄。ABCA 1是胆固醇稳态的主要调节剂。ABCA 1基因突变导致严重的HDL缺乏，其特征是细胞中胆固醇的积累和普遍的动脉粥样硬化。ABCA 1的转录上调由核受体LXR和PPARgamma控制，其显示增加HDL水平并减少体内动脉粥样硬化病变。最近，其他人和我们证明LXR的配体增加了神经元细胞中ABCA 1的表达，并减少了淀粉样蛋白β（ABeta）的分泌。因此，由LXR和PPARgamma的药理学激活触发的ABCA 1的转录上调可减少脑中淀粉样蛋白的产生和斑块形成。我们的建议有两个主要目标：目标1。确定合成的LXR和PPARgamma配体对体外ABCA 1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，以了解它们在体外对ABeta产生的抑制潜力。将在神经元细胞系和原代神经元中确定该效应。目标2.通过比较APP 23/ABCA 1 wt和APP 23/ABCA 1-/-中的AD表型以及通过用LXR和PPARgamma配体进一步治疗这些小鼠来验证ABCA 1作为治疗靶点。该目标有两个主要目标：（1）。确定与APP 23/ABCA 1/wt小鼠相比，ABCA 1的靶向破坏是否影响APP 23/ABCA 1-/-小鼠的APP 23表型，以及2）。为了检查ff LXR和PPARgamma配体通过ABCA 1依赖性机制对ABeta分泌/沉积发挥其作用。我们将比较LXR和PPARgamma激动剂对野生型或破坏ABCA 1基因的APP 23小鼠中AD样病理学的影响。我们将使用两个年龄组：年轻的动物专门研究对ABeta产生的影响，老年小鼠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对控制细胞内胆固醇含量及其在大脑中再分布的基因如何影响APP加工和ABeta沉积的理解。通过LXR/PPARgamma激动剂上调ABCA 1的可能性将建立针对ABCA 1的药理学干预，作为药物开发和发现用于预防和/或减缓阿尔茨海默病进展的新治疗剂的有价值的方法。

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.