阿尔茨海默病（AD）目前尚无修饰疾病病理变化的治疗药物。氧化应激在AD的发生和发展中起重要作用。研究表明Nrf2通路的激活，可以诱导抗氧化物质的表达、降低氧化应激反应。课题组前期研究发现富马酸二甲酯（DMF）可通过激活Nrf2通路改善AD动物模型的突触可塑性，而DMF是否可以改变AD的病理过程和行为学仍未可知。据此，本课题首先对体外与Aβ共培养的细胞和APP/PS1双转基因AD小鼠消除Nrf2基因，观察Nrf2在AD病理条件下对氧化应激的调节作用；之后通过DMF对Nrf2的调节，采用课题组前期研究建立的药物对认知障碍疾病动物模型作用的评估体系，从行为学、电生理学和AD病理学的改变确定DMF对AD小鼠的治疗作用；在此基础上探讨DMF在AD病理条件下对Nrf2的作用机制。本项目的研究成果将为AD的抗氧化治疗策略提供新的思路。

At present there exists no medication for disease modification in Alzheimer’s disease (AD). Oxidative stress plays a crucial role in the pathogenesis of AD. The nuclear transcription factor NF-E2-related factor 2 (Nrf2) has been shown to increase the antioxidant response element (ARE) and reduce oxidative stress. In our preliminary studies we found that dimethyl fumarate (DMF) improved the synaptic plasticity through Nrf2 pathway activation in AD rats. However, the effect of DMF on the pathological process and cognitive function of AD is still unclear. In this study, the anti-oxidative effect of Nrf2 on the pathologic conditions of AD will be observed through two models: 1. the SH-SY5Y cells and primary rat astrocytes which are co-cultured with Aβ will be transfected with Nrf2-siRNA; 2. the APP/PS1 double transgenic mice will cross with the mice lacking Nrf2. The efficacy of DMF in the treatment of AD mice will be evaluated using the evaluation system established by our preliminary studies, which includes Morris water maze, long-term potentiation, and measures of the level of Aβ, tau, and gliosis in the brain. Finally, the pathways causing Nrf2 activation by DMF will be explored further. The results of this study will provide a novel strategy in the anti-oxidative treatment of AD.