IL1RAP调控小胶质细胞功能参与Aβ病理的机制研究

Recently, a genome-wide association study of longitudinal change in brain amyloid burden measured by 18F-florbetapir PET identified a novel association with higher rates of amyloid accumulation in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P=1.38×10-9). In independent cohorts, rs12053868-G was associated with lower cortical 11C-PBR28 PET signal, a marker of microglial activation, suggesting a crucial role of activated microglia in limiting amyloid accumulation. In our preliminary studies, we provided the first evidence that IL1RAP was uniquely expressed by microglia in brain. What’s more, we demonstrated that the expression of IL1RAP might be affected by Aβ levels. Based on these findings, we intend to investigate the impact of IL1RAP rs12053868-G mutations on the expression of IL1RAP in peripheral blood mononuclear cells (PBMCs), and the Aβ clearance of monocytes, as well as the correlation between IL1RAP expression and Aβ clearance. This project will uncover the possible underlying mechanism on how IL1RAP rs12053868-G mutations induce AD. In addition, to fully elucidate the role of IL1RAP in AD pathogenesis, we investigate the impact of Aβ oligomer on the expression in vitro and in vivo first. Besides, we intend to manipulate IL1RAP expression using lentivirus vectors to reveal its modulation on function of microglia as well as AD-related neuropathology and cognitive impairment. The completion of this project will provide theoretical support for early warning and diagnosis of AD, and will offer novel targets for therapy and drug development of this disease via uncovering its underlying pathogenesis.

近期研究发现IL1RAP的rs12053868变异在GWAS水平上与脑内Aβ沉积的纵向变化率显著相关，进一步研究提示小胶质细胞的活性减低是其Aβ沉积速率加快的重要原因。我们前期研究发现IL1RAP在脑内特异性表达于小胶质细胞表面，且其表达和/或功能状态可能受Aβ水平的影响。在此基础上，我们拟比较rs12053868-G携带者和非携带者外周血IL1RAP表达水平及其单核细胞吞噬Aβ能力的差异，以阐明IL1RAP基因rs12053868-G突变参与AD的发病机制。此外，我们拟运用Aβ刺激离体和在体小胶质细胞，观察其对IL1RAP表达水平及其介导的信号通路的影响，同时运用慢病毒为载体的基因过表达/干扰技术，在细胞层面和活体层面对IL1RAP进行靶向干预，研究其对小胶质细胞功能的调控和对AD病理特征及认知功能的影响，以全面阐明IL1RAP参与AD病理进程的分子机制。

近期研究发现IL1RAP的rs12053868变异在GWAS水平上与脑内Aβ沉积的纵向变化率显著相关，进一步研究提示小胶质细胞的活性减低是其Aβ沉积速率加快的重要原因。我们前期研究发现IL1RAP在脑内特异性表达于小胶质细胞表面，且其表达和/或功能状态可能受Aβ水平的影响。本项目历时3年，在前期建立的CABLE数据库基础上，采用Luminex xMAP技术测定脑脊液中Aβ40和Aβ42的含量，并应用多元线性回归模型，以脑脊液中Aβ42的浓度作为结局变量，IL1RAP的rs12053868位点的多态性作为解释变量，发现rs12053868-G携带者脑脊液中Aβ40和Aβ42的水平明显低于非携带者。我们进一步对IL1RAP在AD发病中的作用及机制进行了深入研究，我们应用体内、外实验和APP/PSEN1转基因小鼠模型研究发现：靶向沉默IL1RAP可衰减小胶质细胞对Aβ 的吞噬作用，显著增加AD 小鼠脑内Aβ 病理；而靶向上调IL1RAP 可改善AD 小鼠脑内Aβ 病理及空间学习记忆能力。本项目的研究成果揭示了IL1RAP在AD发生中的作用机制，为AD的防治提供了新靶点。本研究成果在共发表SCI收录论文6篇。本项目研究成果荣获山东省科技进步二等奖1项，山东省医学会科学技术奖三等奖1项。同时本项目共培养博士2名，硕士4名。本项目研究成果已在多家大型三甲医院中推广应用，为后续深入探讨AD 发生机制和防治措施奠定了坚实基础，取得了显著的社会效益。在本项目的支持下，项目负责人于2020年入选山东省“齐鲁卫生与健康杰出青年人才”和青岛市“未来之星”高层次人才培养计划，并获得青岛市青年科技奖荣誉称号。2021年4月荣登神经科学领域全球前2%顶尖科学家“年度影响力”榜单。2022年入选青岛市医疗卫生优青计划。