ABCA1: A Potential Therapeutic Target for AD

描述(申请人提供)：阿尔茨海默病(AD)和动脉粥样硬化具有共同的危险因素。流行病学和临床研究表明，血管危险因素在这两种疾病中可能都很重要。值得注意的是，最近的遗传数据表明，携带一种常见的ATP结合盒转运体A1(ABCA1)基因变异(R219K)的携带者，最初与动脉粥样硬化的严重程度降低有关，但在阿尔茨海默病发病时延迟了年龄。ABCA1是胆固醇稳态的主要调节者。ABCA1基因的突变会导致严重的高密度脂蛋白缺乏，其特征是细胞中胆固醇的积累和普遍存在的动脉粥样硬化。ABCA1的转录上调是由核受体LXR和PPARGamma控制的-在体内显示可以增加高密度脂蛋白水平和减少动脉粥样硬化病变。最近，其他人和我们证明了LXRs的配体增加了神经细胞中ABCA1的表达，减少了淀粉样β蛋白(ABeta)的分泌。因此，由LXRs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。我们的建议有两个主要目标：目的1.确定合成的LXR和PPARγ配体在体外对ABCA1表达和APP加工的影响。我们将在体外筛选一些合成的LXR配体和PPARγ激动剂，以研究它们对ABeta产生的抑制潜力。这种影响将在神经细胞系和原代神经元中确定。目的2.通过比较APP23/ABCA1wt和APP23/ABCA1-/-的AD表型，以及进一步用LXR和PPARγ配体对这些小鼠进行治疗，验证ABCA1作为治疗靶点的有效性。这一目标有两个主要目标：1)。确定与APP23/ABCA1/wt小鼠相比，ABCA1的靶向干扰是否影响APP23/ABCA1-/-小鼠的APP23表型，以及2)。通过ABCA1依赖机制研究LXR和PPARGamma配体对ABeta分泌/沉积的影响。我们将比较LXR和PPARGamma激动剂对野生型或ABCA1基因突变的APP23小鼠AD样病理的影响。我们将使用两个年龄组：年轻的动物专门检查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重新分布的基因如何影响APP处理和ABeta沉积的理解。LXR/PPARγ激动剂上调ABCA1的可能性将使针对ABCA1的药物干预成为药物开发和发现预防和/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.