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

项目摘要/摘要 越来越多的证据表明，表观遗传变化，包括microRNA(MiRNA)失调，起到了作用 到衰老、精神障碍和神经退行性疾病。虽然miRNA功能的调制 已经为几种疾病产生了有希望的临床数据，miRNA在大脑老化和阿尔茨海默氏症中的作用 阿尔茨海默病(AD)尚未得到彻底研究。在AD发病机制中，胰岛素调节失调 信号是显而易见的。Tau和淀粉样β蛋白的异常积聚被认为是启动一种致病 通向公元的级联。鉴于这些蛋白质聚集在AD中的关键作用，调节tau的策略 和淀粉样β蛋白正被积极用作治疗方法。为此目的，我们试图界定 MicroRNAs(MiRNAs)，特别是miR-17-92，在AD的发病机制中。而不是建立一个基于 对于先前已知的蛋白质和概念，我们进行了无偏转录谱实验 并确定miR-17-92是脑老化过程中调节最严重的miRNAs。值得注意的是，我们的 这一发现与美国国立卫生研究院共同基金最近进行的一项里程碑式的研究--组织表达--是一致的 (GTEx)联盟使用11个人脑亚区的数据。我们假设，miR的这种失调- 17-92的表达可能直接参与衰老过程。因此，重要的是要理解 MiR-17-92在脑衰老中的功能作用并试图恢复其水平以改善衰老效应和 AD发病机制。最近越来越多的研究表明，miRNA失调可能导致几个 神经退行性疾病，包括阿尔茨海默病。有趣的是，我们发现miR-17-92调节tau 磷酸化和APP表达水平可能通过调节胰岛素信号转导途径。在此应用程序中， 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 利用新型AAV Tau小鼠模型研究MIR-17-92对学习记忆和AD相关神经病理的影响 和应用程序敲入鼠标模型。此外，我们将使用几种创新的体内方法来研究 MiR-17-92在牛磺酸和Abeta代谢中作用的机制。

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.