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

描述（申请人提供）：APOE 54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LXR 1和LXR 2的转录控制。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，胆固醇代谢是最重要的分泌酶的活动，APP裂解，A？聚集及其从脑中清除。最近，我们和其他人报道了在APP转基因小鼠中缺失LXR靶基因Abca 1会降低内源性小鼠ApoE水平并增加淀粉样蛋白沉积。与APOE 3携带者相比，APOE 4携带者中AD的发生率更高，淀粉样蛋白沉积增加，这可能是在这些患者中观察到的ApoE蛋白水平较低的结果。因此，载脂蛋白E4亚型提供较少的保护，对有毒的A？物种可以想象，其他遗传因素，如LXR响应强代谢信号（如高脂饮食）的转录调控受损，会影响这种风险并促进痴呆症的发展。我们假设LXR对ApoE的转录控制对于改善ApoE 4亚型对淀粉样蛋白沉积和认知能力下降的不利影响至关重要。该假设基于以下观察结果：首先，我们的初步数据表明，在人ApoE靶向替代小鼠中，ApoE 4蛋白水平低于ApoE 3，这与淀粉样蛋白负荷增加相关。此外，用合成的LXR配体T0901317（T0）处理，增加了体外和体内ApoE 4水平，从而减少了两种亚型之间的定量差异。第二，我们和其他小组的研究表明，T0处理APP转基因小鼠可增加ApoE蛋白水平并抑制A？证词第三，我们最近的研究表明，T0治疗加重了高脂饮食对老年APP 23小鼠淀粉样蛋白沉积和认知能力下降的有害影响，这表明T0对AD表型的影响是由于促进A？通过增加ApoE蛋白水平介导的清除。具体目的1：研究活化的LXR配体如何修饰ApoE 3和ApoE 4亚型对A？聚集和清除。具体目标2：表征LXR配体T0901317对以ApoE 3和EpoE 4为背景饲喂正常和西式饮食的APP/PS1 dE 9小鼠中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.