Department of Psychological and Brain Sciences, the Linda and Jack Gill Center for Bimolecular Sciences, Indiana University, Bloomington, IN, 47405, USA.
Department of Fundamental Neurosciences (DNF), University of Lausanne (UNIL), Lausanne, Switzerland.
Sci Rep. 2018 Jun 18;8(1):9251. doi: 10.1038/s41598-018-27527-6.
MicroRNAs (miRs) are 18~23 nucleotides long non-coding RNAs that regulate gene expression. To explore whether miR alterations in tauopathy contribute to pathological conditions, we first determined which hippocampal miRs are altered at the presymptomatic and symptomatic stages of tauopathy using rTg4510 mice (Tau mice), a well-characterized tauopathy model. miR-RNA pairing analysis using QIAGEN Ingenuity Pathway Analysis (IPA) revealed 401 genes that can be regulated by 71 miRs altered in Tau hippocampi at the presymptomatic stage. Among several miRs confirmed with real-time qPCR, miR142 (-3p and -5p) in Tau hippocampi were significantly upregulated by two-weeks of age and onward. Transcriptome studies by RNAseq and IPA revealed several overlapping biological and disease associated pathways affected by either Tau or miR142 overexpression, including Signal Transducer and Activator of Transcription 3 (Stat3) and Tumor Necrosis Factor Receptor 2 (Tnfr2) signaling pathways. Similar to what was observed in Tau brains, overexpressing miR142 in wildtype cortical neurons augments mRNA levels of Glial Fibrillary Acidic Protein (Gfap) and Colony Stimulating Factor 1 (Csf1), accompanied by a significant increase in microglia and reactive astrocyte numbers. Taken together, our study suggests that miR alterations by Tau overexpression may contribute to the neuroinflammation observed in Tau brains.
微 RNA（miRs）是 18-23 个核苷酸长的非编码 RNA，可调节基因表达。为了探讨 tau 病中的 miR 改变是否导致病理状况，我们首先使用 rTg4510 小鼠（Tau 小鼠），一种特征明确的 tau 病模型，确定了 tau 病的前症期和症状期海马 miR 发生了哪些改变。QIAGEN Ingenuity Pathway Analysis（IPA）的 miR-RNA 配对分析显示，71 种在 Tau 海马中改变的 miR 可以调节 401 个基因。通过实时 qPCR 确认的几种 miR 中，Tau 海马中的 miR142（-3p 和-5p）在两周龄及以后显著上调。RNAseq 和 IPA 的转录组研究揭示了几种受 Tau 或 miR142 过表达影响的重叠生物和疾病相关途径，包括信号转导和转录激活因子 3（Stat3）和肿瘤坏死因子受体 2（Tnfr2）信号通路。与在 Tau 脑中观察到的情况类似，在野生型皮质神经元中过表达 miR142 会增加神经胶质纤维酸性蛋白（Gfap）和集落刺激因子 1（Csf1）的 mRNA 水平，同时小胶质细胞和反应性星形胶质细胞的数量显著增加。总之，我们的研究表明，Tau 过表达引起的 miR 改变可能导致 Tau 脑中观察到的神经炎症。
