细胞色素P450还原酶在阿尔茨海默病中的作用及调控研究

Alzheimer's disease (AD) is a clinical common neurodegenerative disease with a gradual increase of memory loss, gradual decline of the cognition ability, language ability and spatial ability, nerve dysfunction, eventually leading to death in patients. As a key enzyme for drug metabolism, cytochrome P450 reductase (CPR) plays an important role in the pathogenesis of AD. CPR can regulate oxidative stress induced in astrocytes activated by β amyloid (Aβ) and inflammatory cytokines through regulation of p38MAPK signaling pathway in neuronal damage. CPR can also regulate learning and memory through long term potentiation(LTP). Analysis on the signaling pathways and transcription factors could help us to find the new targets of CPR participated in the AD and offer a new direction for clinical drug discovery. Given that the central role of CPR plays in drug metabolism and could be easily reverse regulated by the drugs, this study will not only contribute to the optimization of AD patients medication and leading to individualized medication, but also lay the foundation for the drug treatment of AD. Good social and economic benefits would be created after the establishment of drug screening platform.

阿尔茨海默病（Alzheimer's disease， AD）是一种临床上常见的神经退行性疾病，表现为逐渐增加的记忆缺失，病人的认知能力、语言能力、空间辨别能力逐步衰退，神经功能减退，最终导致死亡。作为一种药物代谢关键酶，细胞色素P450还原酶 (cytochrome P450 reductase，CPR) 在AD发病过程中发挥了重要作用。CPR可以通过调控β淀粉样蛋白（Aβ）激活星形胶质细胞引起的氧化应激，调节炎性细胞因子，通过p38MAPK信号通路参与神经元损伤的调控。CPR还可以通过长时程增加调控学习和记忆。分析信号通路和转录因子，为寻找CPR参与AD新的调控靶点奠定基础，有助于为临床药物研发提供新方向。鉴于CPR在药物代谢中的核心作用及其容易被药物反向调节，此项研究将有助于AD患者优化用药及个体化用药，也为治疗AD的药物研发奠定基础，以此建立药物筛选平台，具备良好的社会和经济效益。

阿尔茨海默病（Alzheimer's disease， AD）是一种临床上常见的神经退行性疾病，表现为逐渐增加的记忆缺失，病人的认知能力、语言能力、空间辨别能力逐步衰退，神经功能减退，最终导致死亡。作为一种药物代谢关键酶，细胞色素P450还原酶 (cytochrome P450 reductase，CPR) 在AD发病过程中发挥了重要作用。本研究探讨了Aβ1-42对于星形胶质细胞及神经元毒性的生物学影响，CPR在这个诱导作用过程中的作用及调控机制，同时还揭示了p38MAPK通路调控在其中的重要作用，以及p38MAPK调控对于记忆的影响。通过构建稳定的CPR降低的小鼠模型，研究CYP450-CPR酶系和AD发病的联系及其他与AD病情相关的影响。研究通过调控降低细胞色素P450及CPR，降低CPR表达，对于小鼠甾体激素，主要为睾酮（T）和17β-雌二醇（E2）的转化和灭活的相关调控。综上所述，本研究运用体内体外研究方法，着重探讨了CPR对于AD病情相关的影响及其相应的调控因素。考虑到CPR在药物代谢的核心作用及其易调控性，本研究不仅有益于CPR调控的合理用药及个体化用药，也为加快AD的药物研发提供理论依据。