基于环状RNA探讨三七总皂苷调控快速老化模型小鼠SAMP8脑内β淀粉样蛋白形成的机制研究

Amyliod β-protein (β-AP) plays a crucial role in Alzheimer’s disease(AD). However, the mechanism ofβ-AP production is still unknown. Our previous study has showed that there are 30 differentially expressed circular RNAs (circRNAs) involving in β-AP production using circRNA chip. Among these circRNAs, 6 circRNAs are differentially expressed after Panax notoginseng saponins (PNS) treatment. Based on the above results, we hypothesize that circRNAs contribute to the regulation ofβ-AP production in AD, and PNS can regulate the expressions of circRNAs to inhibit the production ofβ-AP, thereby playing a positive role in the treatment of AD. The current project is aimed to choose 3-5 highly expressed circRNAs and investigate the role of these circRNAs in β-AP production in AD and illuminate its possible mechanisms using molecular biology and behavioral approaches. Furthermore, we will investigate the effect of PNS on circRNAs, thereby inhibiting the production of β-AP. The project will not only provide theoretical and experimental evidence for PNS to treat AD, but also offer several circRNAs as novel targets for development therapeutic agents against AD.

β淀粉样蛋白（β-AP）在阿尔茨海默病（AD）发病中起关键作用。但目前对其形成的分子机制仍不清楚。前期芯片研究发现，有30个差异表达的关键性环状 RNA （circRNA）可能参与β-AP生成调控，其中，与三七总皂苷（PNS）干预相关的circRNA有6个。据此，我们提出假设：在AD的发生发展过程中，circRNA参与了β-AP的生成调控，PNS可通过调控circRNA的表达从而影响β-AP产生，进而发挥其治疗AD作用。本课题拟从中选3～5个差异表达2倍以上的关键性circRNA，采用生化与分子生物学和动物行为学手段，研究这些circRNA参与调控β-AP生成的分子调控机制，在此基础上，研究PNS是否通过调控circRNA的表达来调控β-AP生成进而延缓AD发病，并阐明其机制。为以circRNA为靶点研发防治AD新药提供实验资料，为开发PNS防治AD提供更多的科学依椐。

β淀粉样蛋白（Aβ）在阿尔茨海默病（AD）发病中起关键作用。但目前对其形成的分子机制仍不清楚。环状 RNA (circRNA) 是由一个以上外显子构成的环形RNA 分子。它大量存在于真核细胞中，具有一定的组织、时序和疾病特异性。研究发现，circRNA具有miRNA “海绵”、结合RNA结合蛋白、影响同源转录本稳定性和翻译多肽等诸多生物学功能，并参与肿瘤、心血管疾病、神经系统疾病和糖尿病等疾病的病理过程，这使得circRNA可能成为疾病治疗的潜在靶标。然而，目前对参与AD发生发展的调控β-AP生成的circRNA具体功能的研究罕见报道。在本研究中，我们发现：①与同月龄SAMR1小鼠相比，circRNA-0001743在SAMP8 AD小鼠海马表达显著升高，circRNA-0001824表达显著降低。过表达circRNA-0001743可促进小鼠神经元N2a细胞和SAMP8 AD小鼠模型海马Aβ的产生，损害AD小鼠学习记忆能力；过表达circRNA-0001824可减少小鼠神经元N2a细胞和SAMP8 AD小鼠模型海马Aβ的产生，同时改善AD小鼠学习记忆能力。进一步发现，circRNA-0001743可能通过miR-383-5p/APP通路促进Aβ形成；circRNA-0001824可能通过miR-503-5p/IDE通路抑制Aβ形成。②PNS可抑制circRNA-0001743表达，促进circRNA-0001824表达，从而抑制Aβ形成并改善小鼠学习记忆能力，该作用可能与PNS调控转录因子STAT1有关。本研究为以circRNA为靶点研发防治AD新药提供实验资料，为开发PNS防治AD提供更多的科学依椐。