氧化应激和SIRT1相关调控在铅致阿尔茨海默病样变中的作用

The impacts of oxidative stress and SIRT1-related regulation on the Alzheimer's disease (AD) especially in oxidative lesion field have caused widespread concerns. At the same time, environmental lead (Pb) exposure is an important risk factor on the process of AD and its neurotoxicity is closely associated with oxidative stress, which suggesting that oxidative stress might be involved in the onset of AD induced by Pb. However, some issues regarding the activate pathway of oxidative stress response which might be involved in the onset of AD and also potential effect of SIRT1-related effect on the process of Pb -induced nervous tissue lesion remain to be explored.This subject will be undertaken to first explore the trend on the AD-related pathological changes and abnormal behavior altered by developmental Pb exposure using in-vivo rodents model. Different mice cohorts with selected Pb exposure period and sampling node will be employed to plot the profiles of AD-related changes and possible oxidative damage across the lifespan, and then monitored the role of ROS-induced oxidative stress and Nrf2/ARE signal pathway on nervous lesion in rats and its downstream effects. The change of symbolic signal molecules of SIRT1-related regulation and its outcome will be detected. Combined with in-vitro cell model by resveratrol intervention or target gene silencing, the study will be performed to further investigate and discuss the above hypotheses by activating or inhibiting the effect of these associations to be verified. Based on the above analysis, the molecular regulation mechanism linking between Pb and AD will be discussed. The overall study will provide related evidence directly between the effects of oxidative stress and SIRT1-related regulation in the process of AD and developmental Pb exposure. The above discussion could thereby give scientific basis for the exploration of AD etiology and pathogenesis.

近年来，氧化应激和SIRT1相关调控在阿尔茨海默病（AD）发病中的作用受到广泛关注，特别是基于神经系统氧化损伤的研究；同时，环境铅暴露是AD发病的重要危险因素，而铅的神经毒作用机制与氧化应激密切相关，提示氧化应激可能是铅致机体AD样变进程的中间环节之一。但有关铅致神经损伤机制中氧化应激涉及的调控机制、是否存在SIRT1相关调控效应及其在AD淀粉样变进程中的作用，尚有待研究。本课题拟通过构建小鼠早期铅暴露模型，持续观察AD相关基因的定位、表达趋势及小鼠的行为学改变，研究氧化应激在铅致神经损伤中的作用机制及其下游效应，分析SIRT1相关调控中标志性分子的表达及结局，结合体外实验进行靶基因沉默和白藜芦醇干预研究，对上述效应加以验证，深入探讨铅暴露致AD样变的分子调控机制，以此综合评价铅暴露对氧化应激、SIRT1相关调控的影响及其与AD相关病变的关联，从而为系统阐明AD发病机制提供新的思路。

环境铅暴露是阿尔茨海默病 (AD)发病的重要危险因素，有关铅致神经损伤机制中氧化应激涉及的调控机制、是否存在沉默信息调节因子1 (SIRT1) 相关调控效应及其在AD淀粉样变进程中的作用，尚有待研究。本课题基于发育早期铅暴露致 AD样变的实验基础，首次在动物实验中引入Nrf2/ARE信号通路进行铅的神经毒作用研究，分析了慢性铅暴露对小鼠脑组织Nrf2蛋白的影响及氧化应激效应，并探讨了白藜芦醇干预对铅暴露氧化应激效应的拮抗作用及其与Nrf2/ARE信号通路相关分子的关联，发现白藜芦醇干预可通过促进Nrf2核转位和活化，进而激活 Nrf2-ARE通路并诱导下游GSH限速酶γ-GCS表达、从而逆转机体GSH稳态失衡，对铅暴露小鼠发挥神经保护作用。基于SIRT1相关调控与AD发病进程的关联，探讨了铅暴露小鼠神经细胞SIRT1蛋白核转位现象，发现白藜芦醇可抑制铅暴露小鼠脑组织Aβ的生成，拮抗铅暴露对小鼠空间学习和记忆能力的损伤，首次提出SIRTl相关的氧化应激调控参与了铅暴露致小鼠神经损伤进程。上述结果提示可通过天然植物抗氧化剂干预来活化SIRTl相关的氧化应激信号分子从而拮抗铅的神经毒作用。这将有助于我们对于预防和治疗铅暴露相关的学习记忆障碍及神经退行性变制定新的策略。