LXR and human ApoE isoform effects on AD phenotype: in vitro and in vivo models

描述(申请人提供)：APOE基因54个等位基因的遗传是晚发性AD的主要遗传危险因素。APOE受肝脏X受体LXR1和LXR2的转录调控。LXR是控制胆固醇代谢相关基因表达的转录因子。在大脑中，除了正常的神经功能外，胆固醇代谢对分泌酶活性、APP裂解、A？聚集及其从大脑中的清除。最近，我们和其他人报道了APP转基因小鼠中ABCA1-LXR靶基因的缺失，降低了内源性小鼠的载脂蛋白E水平，并增加了淀粉样蛋白的沉积。与APOE3携带者相比，APOE4携带者AD的发生率更高，淀粉样蛋白沉积增加可能是这些患者中观察到的ApoE蛋白水平较低的结果。因此，ApoE4亚型对毒素A？物种。可以想象，额外的遗传因素，如LXR对强烈代谢信号的反应转录调节受损，如高脂肪饮食，影响这一风险，并加速痴呆的发展。我们假设，LXR对ApoE的转录控制对于改善ApoE4亚型对淀粉样蛋白沉积和认知功能下降的有害影响至关重要。该假说基于以下观察：首先，我们的初步数据表明，在人类ApoE靶向替换小鼠中，ApoE4的蛋白水平低于ApoE3，这与淀粉样蛋白负荷的增加有关。此外，用合成的LXR配体T0901317(T0)治疗可以提高体外和体内的载脂蛋白E4水平，从而缩小两种亚型之间的数量差异。其次，我们和其他研究小组的研究表明，用T0处理APP转基因小鼠可以提高ApoE蛋白水平，抑制A？证词。第三，我们最近的研究表明，T0治疗减轻了高脂饮食对老年APP23小鼠淀粉样蛋白沉积和认知功能下降的有害影响，这表明T0对AD表型的影响是促进A？清除通过增加载脂蛋白E的水平来实现。两个特定的目标被设计来检验这一假说：特定的目标1：研究激活的LXR配体如何改变载脂蛋白E3和载脂蛋白E4亚型对A？聚集和清关。具体目的2：研究LXR配体T0901317对APP/PS1dE9小鼠ApoE3和EpoE4背景下AD表型的影响。

DESCRIPTION (provided by applicant): The inheritance of 54 allele of APOE is a major genetic risk factor for late-onset AD. APOE is under the transcriptional control of Liver X receptors, LXR1 and LXR2. LXR are transcription factors that control the expression of genes involved in cholesterol metabolism. In brain, in addition to normal neuronal function, cholesterol metabolism is of utmost importance for secretase activities, APP cleavage, A? aggregation and its clearance from the brain. Recently we, and others, reported that deletion of Abca1 - an LXR target gene, in APP transgenic mice decreases endogenous mouse ApoE level and increases amyloid deposition. Compared with APOE3 carriers, higher incidence of AD and increased amyloid deposition in APOE4 carriers might be a result of lower ApoE protein levels observed in these patients. Thus, ApoE4 isoform provides less protection against the accumulation of toxic A? species. It is conceivable that additional genetic factors such as impaired transcriptional regulation by LXR in response to strong metabolic signals, like high fat diet, influence this risk and precipitate the development of dementia. We hypothesize that transcriptional control of ApoE by LXR is critical for ameliorating the detrimental effect of ApoE4 isoform on amyloid deposition and cognitive decline. The hypothesis is based on the following observations: First, our preliminary data demonstrate that in human ApoE targeted replacement mice, ApoE4 protein levels are lower than ApoE3 and this correlates with increased amyloid load. In addition, treatment with the synthetic LXR ligand, T0901317 (T0), increases ApoE4 levels in vitro and in vivo thus reducing the quantitative differences between the two isoforms. Second, studies from our and other groups indicated that treatment of APP transgenic mice with T0 increases ApoE protein level and inhibits A? deposition. Third, our recent study demonstrated that T0 treatment alleviates the deleterious effects of high fat diet on amyloid deposition and cognitive decline in older APP23 mice suggesting that the effect of T0 on AD phenotype is a result of facilitated A? clearance mediated through increased ApoE protein level. Two Specific aims are designed to test the hypothesis: Specific aim 1: To examine how the activated LXR ligands modify the effect of ApoE3 and ApoE4 isoforms on A? aggregation and clearance. Specific aim 2: To characterize the effects of LXR ligand T0901317 on AD phenotype in APP/PS1dE9 mice on ApoE3 and EpoE4 background fed normal and Western type of diets.