PRDX3介导的线粒体稳态失衡在阿尔茨海默症发病中的作用机制研究

The pathogenesis of Alzheimer's disease (AD) and its treatment are still not solved. Mitochondrial homeostasis is of great for the study and treatment of AD, however, the regulation of mitochondrial homeostasis in AD remains unknown. A mitochondrial peroxiredoxin, named PRDX3 plays an important role in the regulation of mitochondrial homeostasis. In the early stage, we found that PRDX3 was upregulated in hippocampus of AD patients and AD mice, while PRDX3 protein expression was decreased during normal brain aging. The learning and memory abilities of AD mice in 40% of the calorie restriction group were significantly improved compared with those of the normal diet group, and the proteomic study showed that PRDX3 expression was down-regulated in hippocampus. Therefore, we propose that reducing PRDX3 in hippocampus of AD mouse is of great significance for delaying the onset of AD. The aim of this project was to learn the key transcription factors of PRDX3 during the process of AD and whether the downregulation of PRDX3 in hippocampus of AD mice could delay the happening of AD. To elucidate the PRDX3 regulates mitochondrial homeostasis and downstream signaling pathways in AD.

阿尔茨海默症（AD）的发病机制及其治疗是当前亟需解决的重大科学问题。线粒体稳态失衡参与了AD的发生发展，但精确的分子机制尚不清楚。PRDX3是表达在线粒体内的过氧化物还原蛋白，前期我们研究发现AD转基因小鼠海马区和AD患者PRDX3表达均显著升高，而40%卡路里限制不但可显著改善AD转基因小鼠学习记忆，同时显著下调海马区PRDX3的表达。据此我们推测PRDX3介导了AD发病中的线粒体失衡，进而促进AD的发生发展。本项目拟采用CRISPR亲和纯化原位调节因子、体内立体定位蛋白干扰、线粒体分离纯化和定量蛋白质组学等技术找出AD发病过程中调控PRDX3表达的关键因子，以及PRDX3调控的线粒体稳态失衡在AD发病过程中的关键作用。有望揭示PRDX3在AD发病中的作用机制，为AD的防治提供潜在的分子标靶。

阿尔茨海默症（AD）的发病机制及其治疗是当前亟需解决的重大科学问题。线粒体稳态失衡参与了AD的发生发展，但精确的分子机制尚不清楚。PRDX3是表达在线粒体内的过氧化物还原蛋白，前期我们研究发现AD转基因小鼠海马区和AD患者PRDX3表达均显著升高，而40%卡路里限制不但可显著改善AD转基因小鼠学习记忆，同时显著下调海马区PRDX3的表达。据此我们推测PRDX3介导了AD发病中的线粒体失衡，进而促进AD的发生发展。本项目通过在AD细胞模型和3XTg-AD小鼠模型上降低PRDX3的表达水平评估PRDX3表达下调对神经元细胞及线粒体的影响调控作用。通过细胞水平调节c-Myc的表达改变，可以显著改变PRDX3的表达水平，证明c-Myc是PRDX3的关键调控转录因子。在AD细胞模型中发现PRDX3表达下调可以促进N2a-APPswe细胞神经突触的形成，促进神经元干细胞NE-4C分化为神经元。PRDX3表达下调，N2a-APPswe细胞的抗氧化水平未发生显著改变。蛋白质组学结果发现PRDX3表达下调，调节了PP2A，GSTM2和ANXA2等关键蛋白的表达改变。PRDX3表达降低后，细胞骨架蛋白、神经发育相关蛋白及脂代谢相关蛋白均发生调节改变，可能参与了PRDX3调节的细胞功能改变。同时，GSTM2可能作为细胞质中的抗氧化蛋白，与PRDX3存在功能互补作用。与PRDX3正常表达的AD小鼠比较，在AD模型小鼠中，下调PRDX3的表达，Aβ淀粉样蛋白表达水平未发现显著差异，水迷宫实验和电跳台实验中不同处理组未发现显著差异。蛋白质组学结果发现PRDX3在较老AD小鼠小胶质细胞和星形胶质细胞中表达升高。PRDX3在AD模型小鼠中的具体调控机制，尚需进一步深入研究。