β淀粉样肽 (Aβ)是干性年龄相关性黄斑变性(AMD)中视网膜色素上皮细胞(RPE)下重要的毒性积聚物，导致其变性凋亡。直接靶向Aβ的艾滋海默药物临床试验结果显示其仅对早期患者有效且存在副作用。故从始动环节干预Aβ是较好的RPE保护策略。前期研究发现Aβ的产生受BACE1调控，但该机制尚待讨论。同时，BACE1的转录受甲基转移酶Dnmt1/3a及Sp1调控。故推测，BACE1转录活性增强可导致Aβ生成、沉积增加，该异常过程可能由甲基转移酶失活协同Sp1结合增加共同调控。为证实该假说，拟在RPE光氧化应激模型中，采用基因转染技术调节BACE1水平，检测Aβ含量改变；质谱法检测BACE1启动子甲基化水平；生物信息学预测共同结合位点；染色质免疫沉淀技术检测Sp1与BACE1结合程度，明确甲基转移酶及Sp1正/逆向调控机制；最后体内外阻断Sp1，检测BACE1及Aβ含量，为新药研发寻找有效靶点。

Amyloid beta (Aβ) is an important toxic composition beneath the retinal pigment epithelium (RPE) layer, leading to RPE degeneration and apoptosis. The results of clinical trials on drugs targeting Aβ showed efficacy only in early stage patients with Alzheimer's Disease, along with evident side effects. Thus, anti-Aβ at an early stage might be a better interventional strategy for RPE protection. Our former studies showed that the productive rate of Aβ was determined by BACE1 but the underlying mechanism required further confirmation. Meanwhile, BACE1 transcriptional levels were simultaneously regulated by Dnmt1/3a and Sp1. Based on these observations, we speculated that the enhanced transcription of BACE1, regulated by Dnmt inactivation and increased Sp1 binding, contributed to the overexpression and accumulation of Aβ. To confirm this hypothesis, we established the photo-oxidative model of RPE cells and eventually Aβ levels were quantified after BACE1 inhibition or activation by gene transfection. The levels of differential methylation of CpG islands within the BACE1 promoter after photo-oxidation were quantified by mass spectrometry. The overlapping combinding sites of Dnmt and Sp1 within the BACE1 promoter were predicted by bioinformatics analyses. Chromatin immunoprecipitation assay was used to verify the changes in the Sp1 combinational levels binding to BACE1 promoter. In this way, we aimed to clarify the positive/negative regulation of Dnmt and Sp1 on BACE1 transcription. Finally, the effect of Sp1 inhibitor was investigated to explore its role as new anti-Aβ target drug in retina.