MicroRNA Mouse Models and Alzheimer’s Disease

MicroRNA 小鼠模型和阿尔茨海默病

• 批准号: 10526166
• 负责人: P. Hemachandra Reddy
• 金额: $ 186.23万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526166
• 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; Antibodies; Astrocytes; Autopsy; B-Lymphocytes; Behavior; Binding Sites; Biogenesis; Biological Assay; Biology; Brain; Brain region; C-terminal; Cells; Cerebrospinal Fluid; Chimeric Proteins; Cognitive; Communication; Dendritic Spines; Development; Disease; Disease Progression; Event; Extracellular Fluid; Fibroblasts; Genes; Genomics; Goals; Hippocampus (Brain); Impaired cognition; Individual; Inflammatory Response; Journals; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Late Onset Alzheimer Disease; Learning; Link; Longevity; Luciferases; Memory; Messenger RNA; MicroRNAs; Microarray Analysis; Microglia; Mitochondria; Molecular; Morphology; Mus; Mutant Strains Mice; Neuroglia; Neurons; Outcome; Oxidation-Reduction; Peripheral; Persons; Positioning Attribute; Production; Proteins; Proteomics; Publishing; Reporter; Research; Resources; Serum; Site; Source; Synapses; System; Testing; Tissues; Toxic effect; Transcript; Transgenic Mice; Transgenic Organisms; Transportation; Up-Regulation; Wild Type Mouse; abeta toxicity; aged; amyloid precursor protein processing; base; cognitive function; conditioned fear; density; human disease; hyperphosphorylated tau; improved; in silico; in vivo; insight; mild cognitive impairment; morris water maze; mouse model; mutant; nervous system disorder; neuron loss; neuroprotection; non-demented; novel; novel therapeutics; object recognition; overexpression; protective effect; response; transcriptome sequencing

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.

项目摘要 拟议研究的目的是更好地了解microRNA-455-3p(miR-3P)的影响。 455-3p)在阿尔茨海默病(AD)中。AD是一种进行性神经系统疾病，其特征是 在淀粉样蛋白β(Aβ)的产生和Aβ从受AD影响的脑区清除减少，导致突触 损伤，过度磷酸化tau，线粒体结构和功能变化，炎症反应， 放松对microRNAs(MiRNAs)的管制，以及神经元丢失。MicroRNAs在基因组中调节细胞活动 和蛋白质组水平通过调控靶基因。MicroRNAs还参与细胞间和细胞内的相互作用。 细胞内的通讯和从大脑到细胞外液的运输。在AD状态下， 阿尔茨海默病患者组织内源性miRNAs水平改变，miRNAs释放到外周 系统。非痴呆健康人、受试者血清中全局miRNA分析的初步研究 轻度认知障碍和AD患者发现miR-455-3p随着疾病的发展而上调 进步了。这一上调在其他AD患者的尸检脑中得到证实 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‘端非编码区的靶点，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的表达。在 在APP小鼠中，miR-455-3p也被发现通过减少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miR-455-3p的产生 被抑制，突变型APP和Abeta水平升高。然而，目前尚不清楚其分子机制。 阿尔茨海默病小鼠的神经保护，当miR-455-3p过表达时，阿尔茨海默病小鼠发生了什么机制 MIR-455-3P减少。拟议的研究将调查以下两个目标：1)确定 MIR-455-3P对A-β和线粒体毒性及突触/认知功能障碍的保护作用 2)确定耗竭的miR-455-3P对Aβ和 阿尔茨海默病进展不同阶段的线粒体毒性和认知功能。拟议的研究将 对miR-455-3P撞击有益和有害的分子机制提供新的见解。