MicroRNA-455-3p and Alzheimer's Disease

MicroRNA-455-3p 与阿尔茨海默病

基本信息

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
项目类别：
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&apos Untranslated Regions Abeta clearance Abeta synthesis Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

项目摘要拟议研究的目的是更好地了解microRNA-455-3p的影响（mir-- 455-3p）在阿尔茨海默氏病（AD）中。 AD是一种进行性神经系统疾病，其特征是增加在淀粉样蛋白-β（Aβ）的产生中，从受广告影响的大脑区域的Aβ清除率降低，导致突触损伤，高磷酸化的tau，线粒体结构和功能变化，炎症反应， microRNA（miRNA）和神经元丧失的放松管制。 microRNA调节基因组的细胞事件通过调节靶向基因的蛋白质组学水平。 microRNA还参与了细胞内通信以及从大脑到细胞外液的运输。在广告状态， AD受影响组织中的miRNA的内源性水平变化，miRNA被释放到周围系统。一项初步研究，分析非痴呆健康人血清中的全球miRNA，受试者随着轻度认知障碍，AD患者发现miR-455-3p越来越多地更新为疾病进展。此上调在其他有AD，AD的人的验尸大脑中得到了验证脑脊液，AD成纤维细胞和AD B淋巴细胞以及App转基因小鼠的大脑中。随后的初步研究表明，miR-455-3p是APP基因3'UTR的目标，并且 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 APP小鼠还发现miR-455-3p通过降低裂变来维持健康的线粒体动力学蛋白质并通过增加融合蛋白。相反，当内源性miR-455-3p的产生被抑制，突变应用程序和ABETA水平增加。但是，尚不清楚，分子机制当miR-455-3p过表达时，细胞中的神经保护在细胞中，当miR-时，细胞中发生了什么机制减少了455-3p。拟议的研究将研究以下3个目的：1）确定 miR-455-3p在AD衰老和进展过程中的水平，2）确定miR-455-3p的受保护作用针对Aβ和线粒体毒性和AD进展不同阶段的认知功能障碍，3）确定耗尽的miR-455-3p对Aβ和线粒体毒性和认知功能的影响 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的影响对有利和细腻的影响。