Role of ABCA1 in neurodegeneration

描述（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，但胆固醇代谢影响阿尔茨海默病发病机制仍不确定。此外，人们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ABCA1在AD发病机制中的作用，ABCA1是一种atp结合盒转运体，介导胆固醇外排和高密度脂蛋白（HDL）的产生。ABCA1基因突变导致严重的高密度脂蛋白缺乏，其特征是细胞内胆固醇积累和普遍的动脉粥样硬化。核肝X受体（LXR）配体增加ABCA1水平，并已被证明可以减少体内动脉粥样硬化病变。我们和其他人发现LXR激动剂在体外减少细胞系和原代神经元的A¿分泌。这一提议背后的具体假设是ABCA1影响A¿的沉积和清除。因此，缺乏功能性ABCA1会加重AD的表型。相反，LXR激动剂引发的ABCA1上调将减少脑内斑块的形成。该假设基于以下观察结果：1)我们最近的研究发现，核LXR受体的激动剂T0901317 （TO）可以减少体内A¿的产生；2)我们和其他人已经证明ABCA1过表达会减少体外A¿分泌；3)我们最近的研究表明，APP转基因小鼠ABCA1缺失导致A¿在大脑中的沉积增加。这些发现提示ABCA1在AD发病机制中起作用。他们还建议LXR激动剂可用于预防或治疗阿尔茨海默病。然而，ABCA1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尚不清楚。具体目标旨在全面评估ABCA1在阿尔茨海默病中的作用：目标1。测定ABCA1对A¿产生和清除的影响。目标2。研究ABCA1在APP23/ABCA1小鼠脑脂质稳态中的作用及其与AD表型进展和恶化的关系。目标3。研究LXR配体To对正常和高脂饲料喂养的APP23小鼠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.