Maphis Nicole M, Jiang Shanya, Binder Jessica, Wright Carrie, Gopalan Banu, Lamb Bruce T, Bhaskar Kiran
Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque NM, USA.
Lieber Institute for Brain Development, Baltimore MD, USA.
Front Mol Neurosci. 2017 Mar 17;10:69. doi: 10.3389/fnmol.2017.00069. eCollection 2017.
Increasing evidence suggests that hyperphosphorylation and aggregation of microtubule-associated protein tau (MAPT or tau) correlates with the development of cognitive impairment in Alzheimer's disease (AD) and related tauopathies. While numerous attempts have been made to model AD-relevant tau pathology in various animal models, there has been very limited success for these models to fully recapitulate the progression of disease as seen in human tauopathies. Here, we performed whole genome gene expression in a genomic mouse model of tauopathy that expressed human gene under the control of endogenous human promoter and also were complete knockout for endogenous mouse tau [referred to as 'hTau ' mice]. First, whole genome expression analysis revealed 64 genes, which were differentially expressed (32 up-regulated and 32 down-regulated) in the hippocampus of 6-month-old hTau mice compared to age-matched non-transgenic controls. Genes relevant to neuronal function or neurological disease include up-regulated genes: PKC-alpha (), MECP2 (), STRN4 (), SLC40a1 (), POLD2 (), PCSK2 (), and down-regulated genes: KRT12 (), LASS1 (), PLAT (), and NRXN1 (). Second, network analysis suggested anatomical structure development, cellular metabolic process, cell death, signal transduction, and stress response were significantly altered biological processes in the hTau mice as compared to age-matched non-transgenic controls. Further characterization of a sub-group of significantly altered genes revealed elevated phosphorylation of MECP2 (methyl-CpG-binding protein-2), which binds to methylated CpGs and associates with chromatin, in hTau mice compared to age-matched controls. Third, phoshpho-MECP2 was elevated in autopsy brain samples from human AD compared to healthy controls. Finally, siRNA-mediated knockdown of MECP2 in human tau expressing N2a cells resulted in a significant decrease in total and phosphorylated tau. Together, these results suggest that MECP2 is a potential novel regulator of tau pathology relevant to AD and tauopathies.
越来越多的证据表明，微管相关蛋白tau（MAPT或tau）的过度磷酸化和聚集与阿尔茨海默病（AD）及相关tau蛋白病中认知障碍的发展相关。尽管人们已多次尝试在各种动物模型中模拟与AD相关的tau病理，但这些模型在完全重现人类tau蛋白病中所见的疾病进展方面取得的成功非常有限。在此，我们在一种tau蛋白病的基因组小鼠模型中进行了全基因组基因表达分析，该模型在内源性人类启动子的控制下表达人类基因，并且内源性小鼠tau完全敲除[称为“hTau”小鼠]。首先，全基因组表达分析揭示了64个基因，与年龄匹配的非转基因对照相比，这些基因在6月龄hTau小鼠的海马体中差异表达（32个上调和32个下调）。与神经元功能或神经疾病相关的基因包括上调基因：蛋白激酶C-α（PKC-α）、甲基化CpG结合蛋白2（MECP2）、STRN4、溶质载体家族40成员1（SLC40a1）、DNA聚合酶δ2（POLD2）、前蛋白转化酶枯草溶菌素2（PCSK2），以及下调基因：角蛋白12（KRT12）、长链鞘氨醇合成酶1（LASS1）、组织型纤溶酶原激活剂（PLAT）和神经连接蛋白1（NRXN1）。其次，网络分析表明，与年龄匹配的非转基因对照相比，hTau小鼠中解剖结构发育、细胞代谢过程、细胞死亡、信号转导和应激反应是显著改变的生物学过程。对一组显著改变基因的进一步表征显示，与年龄匹配的对照相比，hTau小鼠中与甲基化CpG结合并与染色质相关的MECP2（甲基化CpG结合蛋白2）的磷酸化水平升高。第三，与健康对照相比，人类AD尸检脑样本中的磷酸化MECP2升高。最后，在表达人类tau的N2a细胞中，siRNA介导的MECP2敲低导致总tau和磷酸化tau显著减少。总之，这些结果表明MECP2是与AD和tau蛋白病相关的tau病理的潜在新型调节因子。
