MicroRNA-455-3p and Alzheimer's Disease

MicroRNA-455-3p 与阿尔茨海默病

• 批准号: 10230768
• 负责人: P. Hemachandra Reddy
• 金额: $ 58.57万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230768
• 关键词: 3' Untranslated Regions; Abeta clearance; Abeta synthesis; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Autopsy; B-Lymphocytes; Behavior; Binding; Binding Sites; Biogenesis; Biological Markers; Blood Circulation; Brain; Brain region; C-terminal; Cell Culture Techniques; Cells; Cerebrospinal Fluid; Chimeric Proteins; Chondrogenesis; Cognitive; Communication; Complementary DNA; DLG4 gene; Disease; Disease Progression; Embryo; Event; Extracellular Fluid; Fibroblasts; Genes; Genomics; Goals; Human Genome; Impaired cognition; Individual; Inflammatory Response; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Late Onset Alzheimer Disease; Luciferases; Malignant Neoplasms; Messenger RNA; MicroRNAs; Microarray Analysis; Mitochondria; Molecular; Mus; Mutant Strains Mice; Neurons; Outcome; Pathogenesis; Pathology; Peripheral; Persons; Positioning Attribute; Production; Proteins; Proteomics; Publishing; Reporting; Research; Resources; Role; Serum; Site; Source; Structure; Synapses; Synaptophysin; System; Testing; Tissues; Toxic effect; Transgenic Mice; Transportation; Up-Regulation; abeta toxicity; aged; amyloid precursor protein processing; base; behavior test; circulating microRNA; cognitive function; hyperphosphorylated tau; in silico; insight; mild cognitive impairment; mouse genome; mouse model; mutant; nervous system disorder; neuron loss; neuroprotection; non-demented; overexpression; postnatal; prenatal; protective effect; response

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 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 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 cells when miR-455-3p is overexpressed and what mechanisms occur in cells when miR- 455-3p is reduced. The proposed research will investigate the following 3 aims: 1) to determine the status of miR-455-3p levels during aging and progression of AD, 2) to determine the protective effects of miR-455-3p against Aβ and mitochondrial toxicities and cognitive dysfunction at different stages of AD progression, and 3) 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.

项目摘要 这项研究的目的是为了更好地了解microRNA-455 - 3p（miR-3p）对细胞增殖的影响。 455 - 3p）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 β淀粉样蛋白（A β）的产生和A β从AD影响的大脑区域的清除减少，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， 在轻度认知障碍和AD患者中，发现随着疾病的进展，miR-455 - 3p越来越多地上调， 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 - 3p是APP基因3'UTR的靶点， miR-455 - 3p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 - 3p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 - 3p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 - 3p过表达时细胞中的神经保护作用以及当miR-455 - 3p过表达时细胞中发生的机制。 455 - 3P减少了。本研究将探讨以下三个目标：1）确定 在衰老和AD进展期间的miR-455 - 3p水平，2）确定miR-455 - 3p的保护作用 针对AD进展的不同阶段的A β和线粒体毒性以及认知功能障碍，以及3） 确定耗尽的miR-455 - 3p对A β和线粒体毒性以及认知功能的影响， AD进展的不同阶段。拟议的研究将为分子机制提供新的见解 miR-455 - 3p的影响有利和有害。