RBM8A结合并稳定LncRNA-MALAT1激活Wnt信号通路在阿尔茨海默病发病机制中的作用

脑内β-淀粉样蛋白（Aβ）沉积是阿尔茨海默病（AD）主要病因，小胶质细胞（MG）失活是导致Aβ清除失衡的重要原因。我们前期工作发现：RNA结合蛋白8A（RBM8A）在AD病人脑组织中表达显著下降，沉默RBM8A后MG的增殖被抑制，凋亡增加，Wnt通路被抑制，Wnt通路中β-catenin表达下降、TCF/LEF转录活性减弱。LncRNA-MALAT1作为关键桥接因子参与调控Wnt通路，过表达RBM8A显著延长LncRNA-MALAT1半衰期。然而，RBM8A/LncRNA-MALAT1如何调控MG在AD中作用机制尚未明确。本研究拟通过体外细胞模型、RBM8A敲除小鼠、AD经典APP/PS1小鼠模型及人体组织标本，利用细胞生物学及分子生物学等方法阐明它们如何通过Wnt信号通路影响小胶质细胞存活，明确RBM8A在AD中的功能及作用机制，为AD的靶向治疗提供新的理论基础和潜在的治疗靶点。

Amyloid-beta protein deposition in the brain is a major cause of Alzheimer's disease (AD). Microglial cell (MG) inactivation can cause inefficient to clear Aβ. Our study found that the expression of RNA-binding protein 8A (RBM8A) in the brain of AD patients was decreased. We also found that knockdown RBM8A inhibit the microglial cell’s proliferation, increase its apoptosis. Meanwhile, the Wnt signal pathway was inhibited. When We knockdown RBM8A expression in microglial cell’s , the β-catenin protein was decreased, the transcription activation of TCF/LEF was reduce. We found that LncRNA-MALAT1 regulated the Wnt signal pathway as a key bridging factor. Overexpression RBM8A could extend LncRNA-MALAT1 half-life. However, how RBM8A and LncRNA-MALAT1 regulate microglial cell in Alzheimer's disease is unclear. In this study, we will elucidate cellular and molecular mechanisms on how RBM8A regulates MG cells through the Wnt signaling pathway in AD using an in vitro model, an RBM8a knockout mouse model, an AD mouse model (APP/PS1) in vivo and human AD tissue samples. Our studies will provide the evidence that abnormal expression of RBM8a is a potential modulator of AD, which could be used as a potential molecular target for developing the treatment of AD in the future.