miR-124通过靶向Notch信号通路在阿尔茨海默氏病中发挥作用的分子机制研究

As a neurodegenerative disorder,Alzheimer's disease(AD) is the most common reason for old people's dementia. Although many microRNAs are found to be changed during progression of AD,their exact functions in vivo still need further investigation. With short life span and easy for genetic manipulation, Drosophila models could recapitulate many features of AD and are powerful tools to study this disease. miR-124 is a kind of microRNA expressed at high levels in the brain. We found that the expression of miR-124 is reduced in AD Drosophila. miR-124 knockout led to Notch signaling activation. It is reported that Notch singaling activation could increase neuronal vulnerability and accelarate neurodegenation, which were found in AD patients.In order to investigate the role of miR-124 in AD, molecular and cellular experiments as well as bioinformatic analysis will be performed to screen for the targets of miR-124 in Notch signaling pathway. We will use Drosophila AD model and mamalian neuronal cells to invesigate the role of miR-124 in AD by targeting Notch signaling molecules. We hope our study could contribute to the understanding of microRNAs in AD and provide new targets for drug desingn in AD prevention and treatment.

阿尔茨海默氏病（AD）是一种慢性神经退行性疾病。果蝇AD模型可表现出 神经退行性病变，是该病的有效研究工具。我们发现神经系统特异高表达的miR-124(一种microRNA)在AD果蝇中显著下降，提示其在该病中的重要作用。研究表明，miR-124水平降低导致Notch信号通路激活。据报道，Notch信号的过度激活可影响神经系统的结构与功能，而AD病人脑组织Notch信号处于激活状态。为阐明miR-124 、Notch和AD三者的关系，本课题拟用生物芯片、生物信息学分析及相关实验，筛选 Notch通路中miR-124的靶基因；通过果蝇AD模型及相应遗传学操作，从在体水平分析miR-124通过抑制Notch信号通路在AD中发挥作用的分子机制；通过体外实验在人和小鼠神经细胞中验证在果蝇中的发现。我们期望本课题的研究能够为以microRNA为靶点的AD干预和治疗研究提供新的思路和药物设计靶点。

阿尔茨海默氏病（Alzheimer's disease, AD）作为一种慢性神经退行性疾病，是人步入老年以后发生痴呆的重要原因。微小RNA （microRNA, miRNA) 可在转录后水平调节基因表达，在AD中发挥了重要作用。miR-124是一种在神经系统高度表达的miRNA,并且从低等的线虫到人高度保守。但其在AD中的作用目前尚不清楚。通过本课题的研究，我们发现miR-124在AD果蝇脑组织中显著下调，提示其在AD中的重要作用。miR-124敲除果蝇表现出攀爬能力受损和寿命缩短的特征。miR-124表达可以改善AD果蝇的疾病表型。通过基因表达谱芯片分析，我们发现Notch信号通路极有可能受到miR-124调控。进一步研究表明，miR-124可靶向作用于Notch的配体Delta和γ分泌酶复合体的重要成员Presenilin（Psn）。通过RNAi的方法抑制Delta表达后，AD果蝇寿命延长，学习记忆能力的损伤得到改善。另外，Notch激活必需的γ分泌酶的抑制剂DAPT也可显著减轻AD果蝇的症状，进一步证实了我们的发现。综上所述，我们的研究表明，miR-124通过靶向Notch信号通路在AD中发挥了保护性作用。这不仅加深了我们对AD发病机制的认识，而且为AD 干预和治疗研究提供新的思路和药物设计靶点。

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