Bouter Yvonne, Kacprowski Tim, Rößler Fanny, Jensen Lars R, Kuss Andreas W, Bayer Thomas A
Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Georg-August-University, Göttingen, Germany.
Research Group Computational Systems Medicine, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan (WZW), Technical University of Munich (TUM), Weihenstephan, Germany.
Front Neurosci. 2020 Sep 10;14:580524. doi: 10.3389/fnins.2020.580524. eCollection 2020.
The transcriptome of non-coding RNA (ncRNA) species is increasingly focused in Alzheimer's disease (AD) research. NcRNAs comprise, among others, transfer RNAs, long non-coding RNAs and microRNAs (miRs), each with their own specific biological function. We used smallRNASeq to assess miR expression in the hippocampus of young (3 month old) and aged (8 month old) Tg4-42 mice, a model system for sporadic AD, as well as age-matched wildtype controls. Tg4-42 mice express N-truncated Aβ, develop age-related neuron loss, reduced neurogenesis and behavioral deficits. Our results do not only confirm known miR-AD associations in Tg4-42 mice, but more importantly pinpoint 22 additional miRs associated to the disease. Twenty-five miRs were differentially expressed in both aged Tg4-42 and aged wildtype mice while eight miRs were differentially expressed only in aged wildtype mice, and 33 only in aged Tg4-42 mice. No significant alteration in the miRNome was detected in young mice, which indicates that the changes observed in aged mice are down-stream effects of Aβ-induced pathology in the Tg4-42 mouse model for AD. Targets of those miRs were predicted using miRWalk. For miRs that were differentially expressed only in the Tg4-42 model, 128 targets could be identified, whereas 18 genes were targeted by miRs only differentially expressed in wildtype mice and 85 genes were targeted by miRs differentially expressed in both mouse models. Genes targeted by differentially expressed miRs in the Tg4-42 model were enriched for negative regulation of long-term synaptic potentiation, learning or memory, regulation of synaptic signaling and modulation of chemical synaptic transmission obtained. This untargeted miR sequencing approach supports previous reports on the Tg4-42 mice as a valuable model for AD. Furthermore, it revealed miRs involved in AD, which can serve as biomarkers or therapeutic targets.
非编码RNA（ncRNA）种类的转录组在阿尔茨海默病（AD）研究中越来越受到关注。ncRNA包括转运RNA、长链非编码RNA和微小RNA（miR）等，每种都有其特定的生物学功能。我们使用小RNA测序来评估年轻（3个月大）和老年（8个月大）的Tg4-42小鼠海马体中的miR表达，Tg4-42小鼠是散发性AD的模型系统，以及年龄匹配野生型对照。Tg4-42小鼠表达N端截短的Aβ，出现与年龄相关的神经元丢失、神经发生减少和行为缺陷。我们的结果不仅证实了Tg4-42小鼠中已知的miR与AD的关联，更重要的是还确定了另外22种与该疾病相关的miR。25种miR在老年Tg4-42小鼠和老年野生型小鼠中均有差异表达，而8种miR仅在老年野生型小鼠中差异表达，33种仅在老年Tg4-42小鼠中差异表达。在年轻小鼠中未检测到miR组有显著变化，这表明在老年小鼠中观察到的变化是Tg4-42 AD小鼠模型中Aβ诱导病理的下游效应。使用miRWalk预测了这些miR的靶标。对于仅在Tg4-42模型中差异表达的miR，可鉴定出128个靶标，而仅在野生型小鼠中差异表达的miR靶向18个基因，在两种小鼠模型中差异表达的miR靶向85个基因。Tg4-42模型中差异表达的miR靶向的基因在长期突触增强、学习或记忆的负调控、突触信号调节和化学突触传递调节方面富集。这种非靶向miR测序方法支持了之前关于Tg4-42小鼠作为AD有价值模型的报道。此外，它揭示了参与AD的miR，可作为生物标志物或治疗靶点。
