Tra2β对RAGE基因可变剪接的调控及对RAGE介导的Aβ神经毒性的影响

RAGE是介导脑内Aβ神经毒性的膜受体，而RAGE基因经可变剪接产生的另一亚型—可溶性分泌型esRAGE能拮抗RAGE的功能。研究显示，esRAGE/RAGE比例失衡与阿尔茨海默病（AD）密切关联。通过干预RAGE基因可变剪接而降低Aβ神经毒性,可能在AD防治中起作用。但RAGE剪接机制尚不清楚。我们前期研究显示，Tra2β参与RAGE可变剪接并上调esRAGE/RAGE比例。在AD脑和细胞模型中，检测到Tra2β表达下调，提示Tra2β可能通过调控RAGE剪接而参与AD发生。因此，本项目将从Tra2β的表达、RAGE基因上的Tra2β高亲和序列方面，研究Tra2β对RAGE剪接的调控机制；并利用模拟AD早期病理的细胞模型，通过干预Tra2β表达，分析Tra2β对RAGE剪接的调控及其对AD早期病理过程中Aβ神经毒性的影响。

The receptor for advanced glycation endproducts (RAGE) gene expresses an important membrane receptor that mediates the neurotoxicity of Aβ in the brain. In addition, by alternative splicing, the gene also expresses another soluble protein isoform of RAGE (esRAGE, endogenous secretary RAGE) that is an antagonist against the function of RAGE and reduces the Aβ-mediated neurotoxicity. An imbalanced esRAGE /RAGE ratio is known to be closely related with Alzheimer’s disease (AD) pathogenesis. Thus, it is hypothesized that restoring the esRAGE/RAGE ratio to normal by interfering the alternative splicing of RAGE gene may decrease the neurotoxicity of Aβ and would provide a new effective strategy in AD prevention and treatment. In preliminary studies, we demonstrated that Tra2β plays an important role in regulating the alternative splicing of RAGE gene and the esRAGE/RAGE ratio. In addition, we also detected the significantly decreased expression of Tra2β proteins in the cell model of AD pathogenesis, and in brain autopsy slices of AD patient, which is consistent with the report showing the abnormal high expression of Tra2β in human postmortem brain tissue of AD patients. These results imply that Tra2β is probably involved in AD pathogenesis through regulating the alternative splicing of RAGE gene, supporting our hypothesis. The aim of this project is to examine the hypothesis by investigating the molecular mechanism underlying the regulation of alternative splicing of the RAGE gene by Tra2β from multiple aspects, including Tra2β over-expression or silence, characterization of nucleic acid sequences critical for Tra2β to bind with RAGE transcripts. Furthermore, we will study the effect of the Tra2β-regulated alternative splicing of the RAGE gene in early AD pathogenesis using the cell model of AD pathogenesis. The results will bring new data to the elucidation of AD pathogenesis and provide a basis for exploring the possibility to develop a new strategy for the prevention and treatment of AD.