Role of ABCA1 in neurodegeneration

描述（由申请人提供）：流行病学和临床研究表明胆固醇代谢与阿尔茨海默病（AD）发病机制之间存在联系。尽管这种联系具有治疗潜力，但胆固醇代谢影响AD发病机制的机制仍不确定。此外，对通过干扰胆固醇代谢来改善AD表型的药物知之甚少。我们一直在研究ABCA 1在AD发病机制中的作用，ABCA 1是一种ATP结合盒转运蛋白，介导胆固醇流出和高密度脂蛋白（HDL）的产生。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。核肝X受体（LXR）的配体增加ABCA 1水平，并已显示出减少体内动脉粥样硬化病变。我们和其他人表明，LXR激动剂减少了体外细胞系和原代神经元中的A？分泌。这一提议背后的具体假设是ABCA 1影响A？沉积和清除。因此，功能性ABCA 1的缺乏将加重AD表型。相反，由LXR激动剂触发的ABCA 1的上调将减少脑中的斑块形成。该假设基于以下观察结果：1）我们最近的研究确定了T0901317（TO），一种核LXR受体激动剂，减少体内A？的产生; 2）我们和其他人已经证明ABCA 1过表达减少体外A？分泌; 3）我们最近的研究表明，APP转基因小鼠中ABCA 1缺乏导致A？在脑中沉积增加。这些发现表明ABCA 1在AD发病机制中起作用。他们还表明，LXR激动剂可用于预防或治疗阿尔茨海默病。然而，ABCA 1表达改变和LXRs治疗在A？加工和AD发病机制中的确切机制和后果仍不清楚。具体目的旨在全面评估ABCA 1在阿尔茨海默病中的作用：目的1。确定ABCA 1对A？产生和清除的影响。目标二。为了表征ABCA 1在脑脂质稳态中的作用，以及这与APP 23/ABCA 1小鼠中AD表型的进展和恶化如何相关。目标3。为了检查LXR配体TO对饲喂正常和高脂肪饮食的APP 23小鼠中的AD表型的影响。

DESCRIPTION (provided by applicant): Epidemiological and clinical studies have suggested a link between cholesterol metabolism and Alzheimer's Disease (AD) pathogenesis. Despite therapeutic potential of this link, mechanisms by which cholesterol metabolism influences AD pathogenesis remain uncertain. Moreover, relatively little is known about drugs that ameliorate AD phenotypes by interfering with cholesterol metabolism. We have been investigating the role of ABCA1, an ATP-binding cassette transporter that mediates cholesterol efflux and generation of high density lipoproteins (HDL), in AD pathogenesis. Mutations in the ABCA1 gene cause severe HDL deficiencies characterized by accumulation of cholesterol in cells and prevalent atherosclerosis. Ligands for Nuclear liver X receptors (LXR) increase ABCA1 levels and have been shown to decrease atherosclerotic lesions in vivo. We and others showed that LXR agonists reduced A¿ secretion in cell lines and primary neurons in vitro. The specific hypothesis behind this proposal is that ABCA1 affects A¿ deposition and clearance. Therefore, lack of functional ABCA1 will aggravate AD phenotype. In contrast, upregulation of ABCA1 triggered by LXR agonists will reduce plaque formation in the brain. The hypothesis is based on the following observations: 1) Our recent study established that T0901317 (TO), an agonist of nuclear LXR receptors, reduces A¿ production in vivo; 2) we and others have demonstrated that ABCA1 overexpression decreases A¿ secretion in vitro; 3) Our most recent studies show that ABCA1 deficiency in APP transgenic mice leads to an increased deposition of A¿ in the brain. These findings suggest that ABCA1 plays a role in AD pathogenesis. They also suggest that LXR agonists may be used to prevent or treat Alzheimer's disease. Yet, precise mechanisms and consequence of altered ABCA1 expression and LXRs treatment in A¿ processing and AD pathogenesis remain unclear. The specific Aims are designed to provide a comprehensive assessment of the role of ABCA1 in Alzheimer's disease: Aim 1. To determine the effect of ABCA1 on A¿ production and clearance. Aim 2. To characterize the role of ABCA1 in brain lipid homeostasis and how this is related to the progression and exacerbation of AD phenotype in APP23/ABCA1"'' mice. Aim 3. To examine the effect of the LXR ligand TO on AD phenotype in APP23 mice fed normal and high fat diet.