lncRNA PVT1-miR-146a调控LRP2的表达在阿尔茨海默病发病中作用的研究

It is well-known that amyloid-beta (Aβ) aggregates is one of the major pathological hallmark of Alzheimer’s disease (AD). In AD patients, mutations of lipoprotein Receptor-related Protein 2(LRP2) gene always cause the structural defects or instability of the protein which makes LRP2 easily degraded, leading to the decreased level of LRP2, subsequent increase the level of Aβ and the development of AD. Reduced LRP2 has also been reported in AD. Because there is no change in the gene sequence, the reduction may be caused by the abnormal regulation of protein expression. MicroRNAs (miRNAs) play important regulatory roles at the post-transcriptional level by targeting mRNAs for cleavage or translational repression. Previous studies have shown that miR-146a plays an important role in regulating the expression of LRP2 protein. In recent years, a competitive RNA (ceRNA) hypothesis has been proposed and several studies have suggested the interaction between lncRNA and miRNA in neurodegeneration diseases. LncRNAs can act as “miRNA sponge” and sequester miRNAs to inactivate these small regulatory RNAs. We also found the expression of lncRNA PVT1 was down regulated in AD model. The aim of our project is to explore a lncRNA-miRNA regulation pathway in the regulation of LRP2 expression and the pathogenesis of Alzheimer’s disease. This project is considered to be of both great scientific importance and potential clinical application and provide a new theoretical basis for the pathogenesis of AD and a new strategy for the treatment of AD.

聚集的淀粉样蛋白(Aβ)是阿尔茨海默病(AD)的最主要病理特征之一。AD患者中低密度脂蛋白受体相关蛋白2（LRP2）基因的突变可引起蛋白结构的缺失或增加蛋白的不稳定性而使其易被降解，导致LRP2蛋白水平下降，从而引起Aβ生成增加和AD的发展。LRP2水平下降的主要原因可能是其表达调控的异常。微小RNA(miRNA)是蛋白转录后修饰的重要机制，前期研究结果显示miR-146a在调控LRP2蛋白表达上起到了重要作用。近年来，长链非编码RNA（lncRNA）与miRNA相互作用的研究更引起了广泛关注，而且前期研究显示lncRNA PVT1在AD模型中表达下调。本项目拟探讨lncRNA PVT1-miR-146a对LRP2的表达调控机制在AD发病中的作用。本课题的开展具有重要的科学意义和临床应用价值，将为AD发病机制提供新的理论依据, 为AD的治疗提新的策略。

聚集的淀粉样蛋白(Aβ)是阿尔茨海默病(AD)的最主要病理特征之一。microRNAs调控在阿AD患者和AD模型中已有报道。最近的研究表明，许多高水平的microRNAs与阿尔茨海默病的发展密切相关。在此，我们研究了miR-146a的作用，miR-146a是一种富含大脑的miRNA，在AD患者中上调。对miR-146a预测靶点的分析确定了低密度脂蛋白受体相关蛋白-（LRP2），LDLR家族的一个成员，已知在AD中起保护作用, AD患者LRP2基因的突变可引起蛋白结构的缺失或增加蛋白的不稳定性而使其易被降解，导致LRP2蛋白水平下降，从而引起Aβ生成增加和AD的发展,LRP2水平下降的主要原因可能是其表达调控的异常。在SH-SY5Y细胞中miR-146a的过度表达显著降低LRP2，导致AKT活化的降低和促凋亡的caspase-3的诱导，细胞凋亡增加。因此，特异的miR-146a调控可能通过下调LRP2/AKT通路参与AD的发生。