Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand; Brain Research, New Zealand - Rangahau Roro Aotearoa.
Brain Research, New Zealand - Rangahau Roro Aotearoa; Department of Anatomy, University of Otago, Dunedin, New Zealand.
Neuroscience. 2019 Jul 15;411:164-176. doi: 10.1016/j.neuroscience.2019.05.036. Epub 2019 May 30.
Pathological accumulation of tau protein in brain cells is the hallmark of a group of neurodegenerative diseases called tauopathies. Accumulation of tau protein begins years before the onset of symptoms, which include deficits in cognition, behavior and movement. The pre-symptomatic phase of tauopathy may be the best time to deliver disease-modifying treatments, but this is only possible if prognostic, pre-symptomatic biomarkers are identified. Here we describe the profiling of blood plasma microRNAs in a mouse model of tauopathy, in order to identify biomarkers of pre-symptomatic tauopathy. Circulating RNAs were isolated from blood plasma of 16-week-old and 53-week-old hTau mice and age-matched wild type controls (n = 28). Global microRNA profiling was performed using small RNA sequencing (Illumina) and selected microRNAs were validated using individual TaqMan RT-qPCR. The area under the receiver operating characteristic curve (AUC) was used to evaluate discriminative accuracy. We identified three microRNAs (miR-150-5p, miR-155-5p, miR-375-3p) that were down-regulated in 16-week-old hTau mice, which do not yet exhibit a behavioral phenotype and therefore represent pre-symptomatic tauopathy. The discriminative accuracy was AUC 0.98, 0.95 and 1, respectively. Down-regulation of these microRNAs persisted at 53 weeks of age, when hTau mice exhibit cognitive deficits and advanced neuropathology. Bioinformatic analysis showed that these three microRNAs converge on pathways associated with neuronal signaling and phosphorylation of tau. Thus, these circulating microRNAs appear to reflect neuropathological change and are promising candidates in the development of biomarkers of pre-symptomatic tauopathy.
在脑细胞中tau 蛋白的病理性积累是一组称为tau 病的神经退行性疾病的标志。tau 蛋白的积累在症状出现前数年就开始了，这些症状包括认知、行为和运动方面的缺陷。tau 病的无症状前阶段可能是提供疾病修饰治疗的最佳时机，但只有确定预后性、无症状前生物标志物才有可能。在这里，我们描述了 tau 病小鼠模型中血浆 microRNA 的分析，以确定无症状前 tau 病的生物标志物。从 16 周龄和 53 周龄 hTau 小鼠以及年龄匹配的野生型对照的血液血浆中分离循环 RNA(n=28)。使用小 RNA 测序（Illumina）进行全基因组 microRNA 分析，并使用单个 TaqMan RT-qPCR 验证选定的 microRNAs。使用接收器操作特征曲线 (ROC) 下的面积来评估区分准确性。我们鉴定了三个在 16 周龄 hTau 小鼠中下调的 microRNAs(miR-150-5p、miR-155-5p、miR-375-3p)，这些小鼠尚未表现出行为表型，因此代表无症状前 tau 病。其区分准确性分别为 AUC 0.98、0.95 和 1。这些 microRNAs 的下调在 53 周龄时仍然存在，此时 hTau 小鼠表现出认知缺陷和晚期神经病理学。生物信息学分析表明，这三个 microRNAs 集中在与神经元信号和 tau 磷酸化相关的途径上。因此，这些循环 microRNAs 似乎反映了神经病理学变化，是无症状前 tau 病生物标志物开发的有希望的候选物。
