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.

项目概要 拟议研究的目的是更好地了解 microRNA-455-3p (miR- 455-3p) 治疗阿尔茨海默病 (AD)。 AD 是一种进行性神经系统疾病，其特征是神经功能增加 淀粉样蛋白-β (Aβ) 的产生以及 AD 影响的大脑区域中 Aβ 的清除减少，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、 microRNA (miRNA) 失调和神经元损失。 MicroRNA 在基因组上调节细胞事件 通过调节目标基因来提高蛋白质组水平。 MicroRNA 也参与相互作用 细胞内通讯以及从大脑到细胞外液体的运输。在 AD 状态下， AD 受影响的组织中 miRNA 的内源水平发生变化，并且 miRNA 被释放到外周 系统。一项分析非痴呆健康人、受试者血清中全局 miRNA 的初步研究 患有轻度认知障碍和 AD 患者发现 miR-455-3p 随着疾病的进展而逐渐上调 进步了。这种上调在其他 AD 患者的死后大脑中得到了证实。 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’UTR 的靶标，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 小鼠中，miR-455-3p 还被发现可以通过减少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 产生时 被抑制，突变体 APP 和 Abeta 水平增加。然而，目前尚不清楚，其分子机制 当 miR-455-3p 过表达时，AD 小鼠的神经保护作用以及当 miR-455-3p 过表达时 AD 小鼠中会发生什么机制 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 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-455-3p 对 Aβ 和 AD 进展不同阶段的线粒体毒性和认知功能。拟议的研究将 为 miR-455-3p 有益和有害影响的分子机制提供新的见解。