microRNA-132/212 deficiency enhances Ab production and senile plaque deposition in Alzheimer's disease triple transgenic mice

The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer's disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1. Overall design: We used RNA-Seq to analyse the hippocampus of 3xTg-AD mice lacking the miR-132/212 cluster as well as Neuro2a cells overexpressing miR-132 mimics.

β淀粉样蛋白（amyloid-β, Ab）代谢（如生成、剪切、清除）的异常调控在阿尔茨海默病（Alzheimer's disease, AD）中发挥核心作用。被认为参与AD病程进展的内源性调控因子中，小型调控性非编码微小RNA（microRNAs, miRs）是重要组成部分。尤为值得注意的是，miR-132/212基因簇在AD患者脑组织中表达显著下调。在既往研究中，我们已证实小鼠体内miR-132/212基因簇缺失会引发记忆损伤，并加剧AD患者中观察到的Tau蛋白病理改变。本研究证实，在三转基因阿尔茨海默病（3xTg-AD）小鼠模型中，miR-132/212基因簇的遗传缺失可促进Ab沉积与淀粉样（老年）斑块形成。本研究通过RNA测序（RNA-Seq）与生物信息学（bioinformatics）分析，鉴定出miR-132/212调控网络中多个已被证实参与Ab代谢调控的基因，包括Tau、丝裂原活化蛋白激酶（Mapk）以及沉默信息调节因子1（Sirt1）。
实验设计：本研究采用RNA测序技术，对缺失miR-132/212基因簇的3xTg-AD小鼠海马体，以及过表达miR-132模拟物的Neuro2a细胞进行转录组分析。