The role of aging-associated microRNAs in Alzheimer's disease

项目总结/摘要 越来越多的证据表明，表观遗传变化，包括microRNA（miRNA）失调，有助于 衰老、精神疾病和神经退行性疾病。虽然miRNA功能的调节 已经为几种疾病、miRNA在大脑衰老和阿尔茨海默氏症中的作用提供了有希望的临床数据， 疾病（AD）尚未得到彻底研究。在AD发病过程中， 信号是显而易见的。假设Tau蛋白和淀粉样蛋白β的异常积累启动了致病性 导致AD的级联。鉴于这些蛋白质聚集在AD中的关键作用，调节tau蛋白的策略 和淀粉样蛋白β正被积极地用作治疗方法。为此目的，我们寻求界定 microRNAs（miRNAs），特别是miR-17-92在AD发病机制中的作用。而不是建立一个假设， 以前众所周知的蛋白质和概念，我们进行了公正的转录组学分析实验 并将miR-17-92确定为脑老化过程中最强烈失调的miRNAs。值得注意的是，我们 这一发现与美国国立卫生研究院共同基金的基因型-组织表达最近的一项具有里程碑意义的研究一致 （GTEx）联盟的数据使用11个人脑子区域。我们假设这种miR- 17-92的表达可能直接促进衰老过程。因此，了解 miR-17-92对脑衰老的功能作用下降，并试图恢复其水平以改善衰老作用， AD发病机制最近越来越多的研究表明，miRNA的失调可能有助于几个 神经退行性疾病，包括AD。有趣的是，我们发现miR-17-92调节tau蛋白， 磷酸化和APP的表达水平可能通过调节胰岛素信号通路。在本申请中， 我们建议研究miR-17-92在认知和阿尔茨海默病中的作用。我们将决定如何 miR-17-92影响新AAV Tau小鼠模型的学习记忆和AD相关神经病理学 和APP基因敲入小鼠模型。此外，使用几种创新的体内方法，我们将研究 miR-17-92在Tau和Abeta代谢中作用的潜在机制。

PROJECT SUMMARY/ABSTRACT Mounting evidence suggests that epigenetic changes, including microRNA (miRNA) dysregulation, contribute to aging, psychiatric disorders and neurodegenerative disorders. Although modulations of miRNA function have generated promising clinical data for several diseases, miRNA’s roles in brain aging and Alzheimer’s disease (AD) have not been investigated thoroughly. During AD pathogenesis, dysregulation of insulin signaling is evident. Abnormal accumulation of Tau and amyloid beta is hypothesized to initiate a pathogenic cascade leading to AD. Given the critical role of these protein aggregations in AD, strategies to modulate tau and amyloid beta are actively being pursued as therapies. Toward that end, we seek to define the role of microRNAs (miRNAs), specifically miR-17-92, in AD pathogenesis. Instead of setting up a hypothesis based on the previously well-known proteins and concepts, we performed unbiased transcriptomics profiling experiments and identified miR-17-92 as the most strongly dysregulated miRNAs during brain aging. Remarkably, our finding is consistent with a recent landmark study by the NIH Common Fund’s Genotype-Tissue Expression (GTEx) consortium’s data using 11 human brain subregions. We hypothesize that such dysregulation of miR- 17-92 expression may directly contribute to aging process. Therefore, it will be critical to understand the functional effect of miR-17-92 decline on brain aging and try to restore its levels to ameliorate aging effect and AD pathogenesis. Mounting studies recently suggests that miRNA dysregulation may contribute to several neurodegenerative disorders, including AD. Interestingly, we found that miR-17-92 regulates tau phosphorylation and APP expression level possibly by modulating insulin signaling pathway. In this application, we propose to investigate the role of miR-17-92 in cognition and Alzheimer’s disease. We will determine how miR-17-92 affects learning and memory and AD-related neuropathology using novel AAV Tau mouse model and APP knock-in mouse model. Furthermore using several innovative in vivo methods, we will investigate the mechanism underlying the role of miR-17-92 in Tau and Abeta metabolism.