MicroRNA Mouse Models and Alzheimer’s Disease

项目摘要 这项拟议研究的目的是更好地了解microRNA-455- 3 p（miR-）的影响 455- 3 p）在阿尔茨海默病（AD）中的作用。AD是一种进行性神经系统疾病，其特征在于 在淀粉样蛋白β（Aβ）的产生和减少Aβ从AD影响的大脑区域的清除中，导致突触 损伤，过度磷酸化的tau，线粒体结构和功能变化，炎症反应， microRNAs（miRNAs）失调和神经元丢失。MicroRNA在基因组水平调控细胞事件 和蛋白质组水平通过调节靶基因。MicroRNA还参与了细胞间和细胞间的 细胞内通讯和从脑到细胞外液的运输。在AD状态中， 在AD影响的组织中，内源性miRNA水平发生变化，并且miRNA被释放到外周血中。 系统一项分析非痴呆健康人血清中总体miRNA的初步研究， 轻度认知障碍和AD患者发现，随着疾病的进展，miR-455- 3 p的表达逐渐上调， 进步了这种上调在另外的AD患者的死后大脑中得到证实， 脑脊液、AD成纤维细胞和AD B-淋巴细胞，以及来自APP转基因小鼠的脑中。 随后的初步研究显示，miR-455- 3 p是APP基因3 'UTR的靶点， miR-455- 3 p水平的增加增强了线粒体生物发生蛋白和突触蛋白。在 在APP小鼠中，miR-455- 3 p也被发现通过减少细胞分裂来维持健康的线粒体动力学。 蛋白质和通过增加融合蛋白。相反，当内源性miR-455- 3 p的产生 抑制，增加突变APP和Abeta水平。然而，目前还不清楚，分子机制， 当miR-455- 3 p过表达时，AD小鼠的神经保护作用以及当miR-455- 3 p过表达时， miR-455- 3 p减少。本研究将探讨以下两个目标：1）确定 miR-455- 3 p对Aβ和线粒体毒性以及突触/认知功能障碍的保护作用 AD进展的不同阶段，以及2）确定耗尽的miR-455- 3 p对Aβ和 线粒体毒性和认知功能在AD进展的不同阶段。拟议的研究将 为miR-455- 3 p有利和有害影响的分子机制提供了新的见解。

Project Summary The purpose of the proposed research is to better understand the impact of microRNA-455-3p (miR- 455-3p) in Alzheimer’s disease (AD). AD is a progressive neurological disorder, characterized by an increase in amyloid-β (Aβ) production and reduced clearance of Aβ from AD-affected brain regions, leading to synaptic damage, hyperphosphorylated tau, mitochondrial structural and functional changes, inflammatory responses, deregulation of microRNAs (miRNAs), and neuronal loss. MicroRNAs regulate the cellular events at genomic and proteomic levels through the modulation of targeted genes. MicroRNAs also participate in inter-and- intracellular communication and the transportation from the brain to extracellular fluids. In an AD state, endogenous levels of miRNAs change in AD affected tissues, and the miRNAs are released into the peripheral system. A preliminary study analyzing global miRNA in the serum of non-demented healthy persons, subjects with mild cognitive impairment and AD patients found miR-455-3p increasingly upregulated as the disease progressed. This upregulation was verified in postmortem brains from additional persons with AD, AD cerebrospinal fluid, AD fibroblasts, and AD B-lymphocytes, and in the brains from APP transgenic mice. Subsequent preliminary studies revealed that miR-455-3p was a target to the 3’UTR of the APP gene and that an increase in miR-455-3p levels enhanced mitochondrial biogenesis proteins and the synaptic proteins. In the APP mice, miR-455-3p also was found to maintain healthy mitochondrial dynamics by decreasing the fission proteins and by increasing the fusion proteins. In contrast, when the production of endogenous miR-455-3p was inhibited, mutant APP and Abeta levels were increased. However, it is unclear, molecular mechanisms of neuroprotection in AD mice, when miR-455-3p is overexpressed and what mechanisms occur in AD mice when miR-455-3p is reduced. The proposed research will investigate the following 2 aims: 1) to determine the protective effects of miR-455-3p against Aβ and mitochondrial toxicities and synaptic/cognitive dysfunction at different stages of AD progression, and 2) to determine the effects of depleted miR-455-3p on Aβ and mitochondrial toxicities and cognitive function at different stages of AD progression. The proposed studies will provide new insights into molecular mechanisms of miR-455-3p impacts beneficially and deleteriously.