长链非编码RNA Rpph1通过竞争性内源RNA机制参与阿尔兹海默症进展的分子机制研究

Alzheimer’s disease (AD) is a chronic neurodegenerative disease affected 36 million aging people worldwide. Aberrant expression of key genes by Aβ aggregation is the most prominent mechanisms underlying Aβ-induced neurotoxicity. We previously found that Aβ can induce expression of microRNAs and play a pivotal role in AD development. However, deregulation of these microRNAs and their roles in the pathological process of AD remains largely unknown. In combination with microRNA and whole transcritome sequencing analysis, we herein constructed a long non-coding RNA (lncRNA)-microRNA interaction network in AD model. In current proposal, we aim to decipher the regulation of microRNAs by lncRNA Rpph1 in a competing endogenous RNA (ceRNA) manner during the progress of AD. We will investigated how Rpph1 binds to microRNA-326-3p/microRNA330-5p and regulates the expression and activity of their downstream target Cdc42 during spine maturation and learning/memory. This findings will not only advance our understanding of “Aβ toxicity theory”, but also provide us a new lncRNA based strategy for treatment of AD.

阿尔兹海默症(AD)是一种严重威胁老年人健康和生活质量的神经退行性疾病。本课题组前期研究发现受Aβ诱导的非编码RNA在AD的进程中发挥重要作用。通过在AD模型小鼠中进行microRNA和全转录组测序以及后续的生物信息学分析，课题组成员构建了长链非编码RNA(lncRNA)-microRNA的调控网络，拟在分子、细胞和动物水平上证明lncRNA Rpph1通过竞争内源性RNA(ceRNA)机制，吸附内源microRNA，调控下游靶蛋白Cdc42的表达和活性，继而影响神经元树突棘的形态功能和AD的学习记忆障碍的发生。本项研究有望揭示AD发生过程中新的分子机制：由Aβ诱导的异常表达的lncRNA通过ceRNA机制调控microRNA网络，导致受microRNA调控的突触相关蛋白功能紊乱。这是对现有Aβ理论的补充，有助于拓宽我们对AD发病机制的理解，而且可能为AD的诊断和治疗提供新的理论线索。

阿尔兹海默症(AD)是一种严重威胁老年人健康和生活质量的神经退行性疾病。本项目通过对AD模型小鼠进行microRNA和全转录组测序的测序分析，构建了一套长链非编码RNA(lncRNA)-microRNA的调控网络，并证实了lncRNA Rpph1通过竞争内源性RNA(ceRNA)机制，吸附内源microRNA-326-3p/microRNA330-5p，调控下游靶蛋白Cdc42的表达和活性，继而影响神经元树突棘的形态功能，进而可能参与了AD的发生发展过程。本项研究揭示AD发生过程中新的分子机制：Aβ诱导的异常表达的lncRNA通过ceRNA机制调控microRNA网络，导致受microRNA调控的突触相关蛋白功能紊乱。这是对现有Aβ理论的补充，有助于拓宽我们对AD发病机制的理解，而且可能为AD的诊断和治疗提供新的理论依据。