microRNA-758-3p in cognition and Alzheimer's Disease

项目摘要/摘要 淀粉样蛋白β(Aβ)多肽在寡聚体和较大聚集体中的异常堆积被认为是 引发导致阿尔茨海默病(AD)的致病级联反应。鉴于Aβ在AD中的关键作用 阿尔茨海默病的发病机制、调节Aβ产生和清除的策略正在积极探索 治疗。为此，我们试图定义microRNAs(MiRNAs)，特别是miR-758在AD中的作用 发病机制。越来越多的证据有力地表明，miRNA失调可能是导致 神经退行性疾病，包括阿尔茨海默病。我们最近发现，A-β可诱导脑功能丰富的MIR-758 MiR-758可增加Aβ水平。在这个应用中，我们建议研究miR- 使用原代神经元细胞(AIM 1)和APP/PS1在认知和阿尔茨海默病中的作用 转基因小鼠模型(目标2)。我们将确定miR-758的过度表达是否会损害学习 在APP/早老性小鼠模型中，通过增加毒性Aβ，记忆和触发神经细胞死亡 在大脑中积累。如果是这样的话，这个小鼠品系将是测试神经保护的一个有价值的模型系统 体内治疗，克服了几乎所有APP小鼠模型中缺乏明显的细胞死亡。

PROJECT SUMMARY/ABSTRACT Abnormal accumulation of amyloid β (Aβ) peptide into oligomers and larger aggregates is hypothesized to initiate a pathogenic cascade leading to Alzheimer’s disease (AD). Given the critical role of Aβ in AD pathogenesis, strategies to modulate Aβ production and clearance are actively being pursued as AD therapies. Toward that end, we seek to define the role of microRNAs (miRNAs), specifically miR-758, in AD pathogenesis. Mounting evidence strongly suggests that miRNA dysregulation may contribute to neurodegenerative disorders, including AD. We recently found that Aβ induces brain-enriched miR-758 expression and miR-758 increases Aβ levels. In this application, we propose to investigate the role of miR- 758 in cognition and Alzheimer’s disease by using primary neuronal cells (Aim 1) and an APP/PS1 transgenic mouse model (Aim 2). We will determine whether overexpression of miR-758 impairs learning and memory and trigger neuronal cell death in an APP/presenilin mouse model by increasing toxic Aβ accumulation in brain. If so, this mouse line will be a valuable model system to test neuroprotective therapeutics in vivo, overcoming the lack of overt cell death in almost all APP mouse models.