下调miR-138表达对阿尔茨海默病的保护作用及机制研究

项目名称： 下调miR-138表达对阿尔茨海默病的保护作用及机制研究

项目编号： No.81500925

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王雄

作者单位： 华中科技大学

项目金额： 17.5万元

中文摘要： 细胞外的淀粉样蛋白β（Aβ）沉积是阿尔茨海默病(AD)的早期病理改变。MiR-138是一种脑内富集，能负向调节突触形态发生的microRNA，并在AD病人脑内表达显著升高。我们发现miR-138在12月龄AD转基因小鼠以及细胞模型中表达升高，并通过抑制维甲酸受体α表达促进tau蛋白磷酸化。此外，miR-138也能显著增加Aβ水平，但其具体机制尚不明确。本项目基于前期研究，拟通过在4月龄Tg2576转基因小鼠以及过表达淀粉样蛋白前体蛋白（APP）的N2a/APP细胞中研究miR-138对Aβ生成的影响及其分子机制。最后在12月龄Tg2576小鼠海马中注射miR-138抑制剂或其靶基因的过表达腺病毒，运用ELISA，免疫组化，高尔基染色，水迷宫等技术研究下调miR-138或上调其靶基因表达对12月龄Tg2576小鼠AD样Aβ沉积和学习记忆障碍的保护作用，该项目研究结果有望为AD防治提供新靶点。

中文关键词： 阿尔茨海默病；miR-138；beta淀粉样蛋白；学习记忆；Tg2576

英文摘要： Amyloid-β (Aβ) deposition is an early pathological hallmark of Alzheimer's disease (AD). MiR-138, a brain-enriched microRNA, negatively regulates dendritic spine morphogenesis, and is significantly increased in brains of AD patients. Our previous work found that miR-138 was elevated in the hippocampus of 12-month-old AD transgenic mice (Tg2576 mice) as well as cell models. Forced overexpression of miR-138 promoted tau phosphorylation by targeting retinoic acid receptor α (RARA). In addition, miR-138 also remarkably increased Aβ production, but the underling mechanism was not clear. This application is based on our previous work, and proposes to investigate the effect of miR-138 on Aβ production and the underlying molecular mechanisms in both 4-month-old Tg2576 mice and N2a/APP cell line, which stably expresses human amyloid precursor protein (APP). Furthermore, ELISA, immunohistochemistry, Golgi staining, and Morris Water Maze will be used to study the protective effects of strategies targeting miR-138 or its target gene on Aβ production and deposition, learning and memory defect in 12-month Tg2576 mice by injecting miR-138 antagomir or its target gene overexpressed via Adeno-associated virus(AAV) into the hippocampus of 12-month-old Tg2576 mice. The results of this project may reveal new strategies for prevention and treatment of AD.

英文关键词： Alzheimer's disease;miR-138;Aβ;learning and memory;Tg2576