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

• 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
• 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' 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

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.

项目概要 阿尔茨海默病 (AD) 和相关 tau 病的一个常见病理特征是丰富的 脑实质中存在高度磷酸化 tau 蛋白的异常聚集。因为 绝大多数此类病例（晚发型）的病因尚不清楚，目前尚无有效的治疗方法 针对它们的预防措施或治疗方法。考虑到数量不断增加 受这些疾病影响的个体有一种紧迫感，需要确定造成这些疾病的机制 他们的神经病理学表型的发生和发展。 最近，小非编码 RNA，也称为 microRNA (miRNA)，已成为重要的后 参与神经变性的几个关键细胞过程的转录主调节因子。 文献中一致的数据表明 miRNA 在 AD 和相关 tau 病中失调。 然而，由于这些研究通常评估疾病演变中的单个时间点，因此他们没有 确定这些变化是在病理发生之前还是之后发生的。使用公正的方法，在 我们的初步研究发现，特定基因的表达水平随年龄而增加。 miRNA，miRNA22-3p，位于相关 tau 蛋白病小鼠模型早期阶段的海马中 表型。重要的是，我们在死后人类 tau 蛋白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。其他研究表明该 miRNA 直接 调节病理性 tau 积累。该研究计划的层次假设是 miRNA22- 3p 通过调节 tau 相关的特定靶点直接促进 tau 病的发病机制 代谢途径，其水平的调节代表了一种新的治疗方法 治疗这些疾病。 为了检验我们的假设，我们将在相关 tau 蛋白病小鼠模型中过度表达 miRNA22-3p（具体目标 1) 并下调同一模型中的 miRNA22-3p 表达水平（具体目标 2）。为了建立 其细胞来源及其对 tau 表型的贡献，我们将用细胞生成 tau 病小鼠模型 特定 miRNA22-3p 缺陷（特定目标 3）。在所有这些模型中，我们将评估其影响并 操纵这种特定 miRNA 水平对 tau 神经病理表型和认知的机制 功能。 总体而言，我们研究计划的长期目标是确定 miRNA22-3p 在 AD 和相关 tau 病的病理生理学，并最终通过确定其生物学靶标来 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。