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

描述（由申请人提供）：APOE 54等位基因的遗传是迟发性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，除了正常的神经元功能外，胆固醇代谢对分泌酶活性、APP切割、A？聚集和从大脑中清除。最近，我们和其他人报道了APP转基因小鼠中LXR靶基因Abca1 -的缺失会降低小鼠内源性ApoE水平并增加淀粉样蛋白沉积。与APOE3携带者相比，APOE4携带者较高的AD发病率和淀粉样蛋白沉积增加可能是ApoE蛋白水平较低的结果。因此，ApoE4异构体对有毒A？物种。可以想象，其他遗传因素，如LXR对强代谢信号的转录调节受损，如高脂肪饮食，影响了这种风险，并促使痴呆的发展。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能力下降的有害影响至关重要。该假设基于以下观察结果：首先，我们的初步数据表明，在人类ApoE靶向替代小鼠中，ApoE4蛋白水平低于ApoE3，这与淀粉样蛋白负荷增加有关。此外，用合成的LXR配体T0901317 （T0）处理后，在体外和体内增加ApoE4水平，从而减少了两种异构体之间的数量差异。其次，我们和其他组的研究表明，T0处理APP转基因小鼠可提高ApoE蛋白水平，抑制A？沉积。第三，我们最近的研究表明，T0治疗减轻了高脂肪饮食对老年APP23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表型的影响是促进a ？通过增加ApoE蛋白水平介导的清除。设计了两个特定目标来验证这一假设：特定目标1：研究活化的LXR配体如何改变ApoE3和ApoE4亚型对A？聚集和清除。目的2：研究LXR配体T0901317对ApoE3和EpoE4背景的APP/PS1dE9小鼠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.