Alzheimer's tauopathy phenotype and the microRNA22-3p: implication for pathogenesis

阿尔茨海默病 tau 蛋白病表型和 microRNA22-3p：对发病机制的影响

基本信息

批准号：
10282121
负责人：
DOMENICO PRATICO
金额：
$ 46.27万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10282121
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Astrocytes Autophagocytosis Autopsy Behavioral Biological Brain Brain Diseases Cell physiology Cells Clinical Communities Data Dementia Dependovirus Development Disease Disease Progression Elderly Etiology Event Evolution Excision Functional disorder Gene Delivery Genetic Transcription Goals Hippocampus (Brain)Human Impairment Individual Literature Mediating Memory Loss Memory impairment Metabolic Pathway Metabolism MicroRNAs Microglia Modeling Mus Nerve Degeneration Neuraxis Neurobiology Neurodegenerative Disorders Neurons Onset of illness Organ Paper Pathogenesis Pathogenicity Pathologic Pathology Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Pick Disease of the Brain Play Preventive measure Process Progressive Supranuclear Palsy RNA Splicing Regulation Research Research Proposals Role Secondary to Source Synapses Tauopathies Testing Therapeutic Time Transgenic Mice Untranslated RNA abnormally phosphorylated tau age related base behavioral impairment brain health brain parenchyma brain tissue clinical phenotype cognitive function corticobasal degeneration disease phenotype effective therapy hTau Mice interest mouse model neuroinflammation neuropathology novel novel therapeutic intervention novel therapeutics organ growth overexpression prevent programs small molecule synaptic function tau Proteins tau aggregation tau phosphorylation tau-1 therapeutically effective tool

项目摘要

PROJECT SUMMARY One common pathologic hallmark of Alzheimer's disease (AD) and related tauopathies is the abundant presence of abnormal aggregates of highly phosphorylated tau protein in the brain parenchyma. Because the etiology of the vast majority of these cases (late-onset) is not known, currently there are no effective preventative measures or therapeutic approaches against them. Considering the increasing number of individuals affected by these disorders there is a sense of urgency to identify the mechanisms responsible for the onset and development of their neuroptahologic phenotype. Recently, small non-coding RNAs, also called microRNAs (miRNAs), have emerged as important post- transcriptional master regulators of several key cellular processes involved in neurodegeneration. Consistent data in the literature showed that miRNAs are dysregulated in AD and related tauopathies. However, since these studies typically assessed a single time point in the disease evolution they did not address whether the changes antecede or follow the onset of the pathology. Using an unbiased approach, in our preliminary studies we discovered an age-dependent increase in the expression levels of a specific miRNA, miRNA22-3p, in the hippocampus of a relevant mouse model of tauopathy at an early stage of its phenotype. Importantly, we confirmed this observation also in post-mortem human tauopathy brain tissues when compared with age-matched healthy controls. Additional studies revealed that this miRNA directly modulates pathologic tau accumulation. The hierarchical hypothesis of this research program is that miRNA22- 3p directly contributes to the tauopathy pathogenesis through regulation of specific targets involved in tau metabolic pathways, and that the modulation of its level represents a new therapeutic approach for the treatment of these diseases. To test our hypothesis, we will over-express miRNA22-3p in a relevant tauopathy mouse model (Specific Aim 1) and down-regulate miRNA22-3p expression levels in the same model (Specific Aim 2). In order to establish its cellular source and contribution to the tau phenotype, we will generate tauopathy mouse models with cell- specific miRNA22-3p deficiency (Specific Aim 3). In all these models we will assess the effects and mechanisms of manipulating this specific miRNA level on tau neuropathologic phenotype and cognitive functions. Overall the long-term goal of our research proposal is to establish the functional role that miRNA22-3p plays in the pathophysiology of AD and related tauopathies, and ultimately by identifying its biological targets to develop novel and viable therapeutic tools and strategies against these devastating diseases.

项目摘要阿尔茨海默氏病（AD）和相关tauopathies的一个常见病理标志是丰富脑实质中高度磷酸化的tau蛋白的异常聚集体存在。因为这些病例中绝大多数的病因（晚期）尚不清楚，目前尚无有效的预防措施或治疗方法针对它们。考虑增加的数量受这些疾病影响的个人有一种紧迫感，可以识别负责的机制他们的神经纳学表型的发作和发展。最近，小型非编码RNA，也称为microRNA（miRNA），已经成为重要的后神经退行性的几个关键细胞过程的转录主调节剂。文献中的一致数据表明，在AD和相关的tauopathies中，miRNA失调。但是，由于这些研究通常评估了疾病进化中的一个时间点，因此解决这些变化是在病理学的开始还是遵循病理的开始。使用公正的方法我们的初步研究我们发现了特定的表达水平的年龄依赖性 miRNA，miRNA22-3p，在相关小鼠tauopathy小鼠模型的海马中表型。重要的是，我们在验尸后的人类双性病脑组织中也证实了这一观察结果与年龄匹配的健康对照相比。其他研究表明，这个miRNA直接调节病理性的tau积累。该研究计划的分层假设是miRNA22- 3P直接通过调节涉及tau的特定靶标有助于扭曲的发病机理代谢途径，其水平的调节代表了一种新的治疗方法这些疾病的治疗。为了检验我们的假设，我们将在相关的tauopathy小鼠模型中过度表达miRNA22-3P（特定的目的 1）和下调MiRNA22-3P表达水平在同一模型中（特定目标2）。为了建立它的细胞来源和对tau表型的贡献，我们将生成带有细胞的tauopathy小鼠模型特定的miRNA22-3p缺陷（特定目标3）。在所有这些模型中，我们将评估效果和在TAU神经病理表型和认知方面操纵这种特定miRNA水平的机制功能。总体而言，我们的研究建议的长期目标是确定miRNA22-3P在 AD和相关的tauopathies的病理生理学，最终通过确定其生物学靶标的开发针对这些毁灭性疾病的新颖且可行的治疗工具和策略。