铝应用广泛，影响认知功能，是神经退行性疾病一个重要的环境致病因子。神经元mtDNA氧化损伤，与认知障碍有因果关联，BRCA1可能在其中发挥重要的调控作用，但机制尚未阐明。在我们前期研究发现铝致氧化应激，引起PKA/CREB、Nrf2/ARE通路改变，而橡黄素干预改善学习记忆的基础上，本研究进一步提出假说：铝可产生过多ROS，引起mtDNA氧化损伤，通过干扰活动依赖性CREB、BDNF调控BRCA1的表达，进而影响BRCA1调控BER途径关键酶及Nrf2/ARE通路抗氧化酶的转录，造成mtDNA损伤累积和线粒体功能障碍，最终损害认知功能。本研究拟采用体内、体外试验相结合的方法，应用神经行为学、电生理学、分子生物学等技术手段，从信号通路、蛋白间相互作用、转录调控等不同层面来验证上述假说。本项目将为深入阐明铝损害认知功能的机制，并为寻找早期干预铝相关神经退行性疾病的分子靶点提供新的线索和依据。

Aluminum, which is widely used and can impair cognitive function, is an important environmental pathogenic factor of neurodegenerative disorders. The oxidative damage to mitochondrial DNA of neurons is causally associated with cognitive impairment. Breast cancer susceptibility gene 1 (BRCA1) might play an important role against mitochondrial DNA oxidative damage. However, the mechanism of BRCA1 regulation system is not clear till now. Based on the findings of our previous work that aluminum could induce oxidative stress and interfere PKA/CREB as well as Nrf2/ARE pathway, meanwhile, quercetin could improve learning and memory ability impaired by aluminum, we further put forward the hypothesis here that aluminum could induce excessive ROS, cause oxidative damage to mtDNA, through interfering with the activity-dependent BRCA1 expression mediated by CREB and BDNF, then influencing the transcriptional activation of BRCA1-mediated BER enzymes and Nrf2/ARE-dependent genes against mitochondria oxidative damage, thus induce the accumulation of mtDNA damage and mitochondrial dysfunction, therefore, ultimately injury cognitive function. We plan to conduct in vitro and in vivo experiments by the techniques in neuroethology, electrophysiology, biochemistry and molecular biology to validate the hypothesis mentioned above from the aspects of signaling pathway, the interaction between proteins along with transcription regulation. This grant will provide new evidence and clue for further clarifying the mechanism underlying cognitive impairment caused by aluminum and searching the potential therapeutic molecular targets for early effective intervention against aluminum-related neurodegenerative disorders.