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

项目摘要 阿尔茨海默病（AD）和相关tau蛋白病的一个常见病理学标志是大量的 脑实质中存在高度磷酸化的tau蛋白的异常聚集体。因为 这些病例中绝大多数的病因（晚发性）尚不清楚，目前尚无有效的 预防措施或治疗方法。考虑到越来越多的 受这些疾病影响的个人有一种紧迫感，以确定负责的机制 其神经病理表型的发生和发展。 最近，小的非编码RNA，也被称为microRNA（miRNAs），已经成为重要的后- 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蛋白病中失调。 然而，由于这些研究通常评估疾病演变中的单个时间点， 说明这些变化是在病理发生之前还是之后。使用无偏的方法，在 我们的初步研究发现，一种特定的 在tau蛋白病的相关小鼠模型的海马中的miRNA，miRNA 22 - 3 p，在其早期阶段， 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组相比。进一步的研究表明，这种miRNA直接 调节病理性tau积聚。该研究计划的分层假设是，miRNA 22- 3 p通过调节tau蛋白相关的特异性靶点直接参与tau蛋白病的发病机制 代谢途径，其水平的调节代表了一种新的治疗方法， 这些疾病的治疗。 为了检验我们的假设，我们将在相关的tau蛋白病小鼠模型中过表达miRNA 22 - 3 p（Specific Aim 1)并在相同模型中下调miRNA 22 - 3 p表达水平（特异性目的2）。为了建立 其细胞来源和对tau表型的贡献，我们将产生具有细胞- 特异性miRNA 22 - 3 p缺陷（特异性目标3）。在所有这些模型中，我们将评估影响， 操纵这种特异性miRNA水平对tau神经病理表型和认知功能的作用机制 功能协调发展的 总的来说，我们研究计划的长期目标是确定miRNA 22 - 3 p在细胞凋亡中的功能作用。 AD和相关tau蛋白病的病理生理学，并最终通过鉴定其生物学靶点， 开发新的和可行的治疗工具和战略，以对付这些毁灭性的疾病。

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.