Role of ABCA1 in neurodegeneration

流行病学和临床研究表明胆固醇代谢和阿尔茨海默氏症之间存在联系 疾病（AD）发病机制。尽管这种联系具有治疗潜力，但胆固醇 代谢对AD发病机制的影响尚不清楚。此外，人们对毒品的了解相对较少 通过干扰胆固醇代谢来改善AD表型。 我们一直在研究ABCA 1的作用，ABCA 1是一种ATP结合盒转运蛋白， 胆固醇流出和高密度脂蛋白（HDL）的产生，在AD发病机制。突变 ABCA 1基因导致严重的HDL缺乏，其特征是胆固醇在细胞中积累， 动脉粥样硬化核肝X受体（LXR）的配体增加ABCA 1水平， 显示出减少体内动脉粥样硬化病变。我们和其他研究表明，LXR激动剂可降低Ap 在体外细胞系和原代神经元中的分泌。这一提议背后的具体假设是， ABCA 1影响Ap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的上调将减少斑块 形成大脑。该假设基于以下观察：1）我们最近的研究 建立了T0901317（TO），一种核LXR受体激动剂，减少体内Ap的产生; 2）我们 和其他人已经证明ABCA 1过表达在体外减少Ap分泌; 3）我们最多的研究表明， 最近的研究表明，APP转基因小鼠中ABCA 1的缺乏导致Ap沉积增加， 大脑这些发现表明ABCA 1在AD发病机制中起作用。他们还认为LXR 激动剂可用于预防或治疗AD。然而，ABCA 1改变的确切机制和后果 LXRs在Ap加工和AD发病机制中的表达和LXRs治疗仍不清楚。 具体目标旨在全面评估ABCA 1在AD中的作用： 目标1.确定ABCA 1对Ap产生和清除的影响。目标2.描述的角色 ABCA 1在脑脂质稳态中的作用及其与AD进展和加重的关系 APP 23/ABCA 1-/-小鼠中的表型。目标3。为了检测LXR配体TO对AD表型的影响， 喂食正常和高脂肪饮食的APP 23小鼠。

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 Ap secretion in cell lines and primary neurons in vitro. The specific hypothesis behind this proposal is that ABCA1 affects Ap 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 Ap production in vivo; 2) we and others have demonstrated that ABCA1 overexpression decreases Ap secretion in vitro; 3) Our most recent studies show that ABCA1 deficiency in APP transgenic mice leads to an increased deposition of Ap 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 AD. Yet, precise mechanisms and consequence of altered ABCA1 expression and LXRs treatment in Ap processing and AD pathogenesis remain unclear. The specific aims are designed to provide a comprehensive assessment of the role of ABCA1 in AD: Aim 1. To determine the effect of ABCA1 on Ap 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 TOon AD phenotype in APP23 mice fed normal and high fat diet.