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论文题目: MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer's disease
英文论文题目: MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer's disease
第一作者: Wang, G; Huang, Y; Wang, LL; Zhang, YF; Xu, J; Zhou, Y; Lourenco, GF; Zhang, B; Wang, Y; Ren, RJ; Halliday, GM; Chen, SD
英文第一作者: Wang, G; Huang, Y; Wang, LL; Zhang, YF; Xu, J; Zhou, Y; Lourenco, GF; Zhang, B; Wang, Y; Ren, RJ; Halliday, GM; Chen, SD
联系作者: Chen, SD (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Lab Neurodegenerat Dis, Shanghai 200025, Peoples R China.
英文联系作者: Chen, SD (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Lab Neurodegenerat Dis, Shanghai 200025, Peoples R China.
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发表年度: 2016
卷: 6
期:
页码: 26697
摘要: MicroRNA-146a is upregulated in the brains of patients with Alzheimer's disease (AD). Here, we show that the rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is a target of microRNA-146a in neural cells. Knockdown of ROCK1 mimicked the effects of microRNA-146a overexpression and induced abnormal tau phosphorylation, which was associated with inhibition of phosphorylation of the phosphatase and tensin homolog (PTEN). The ROCK1/PTEN pathway has been implicated in the neuronal hyperphosphorylation of tau that occurs in AD. To determine the function of ROCK1 in AD, brain tissue from 17 donors with low, intermediate or high probability of AD pathology were obtained and analyzed. Data showed that ROCK1 protein levels were reduced and ROCK1 colocalised with hyperphosphorylated tau in early neurofibrillary tangles. Intra-hippocampal delivery of a microRNA-146a specific inhibitor (antagomir) into 5xFAD mice showed enhanced hippocampal levels of ROCK1 protein and repressed tau hyperphosphorylation, partly restoring memory function in the 5xFAD mice. Our in vitro and in vivo results confirm that dysregulation of microRNA-146a biogenesis contributes to tau hyperphosphorylation and AD pathogenesis, and inhibition of this microRNA could be a viable novel in vivo therapy for AD.
英文摘要: MicroRNA-146a is upregulated in the brains of patients with Alzheimer's disease (AD). Here, we show that the rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is a target of microRNA-146a in neural cells. Knockdown of ROCK1 mimicked the effects of microRNA-146a overexpression and induced abnormal tau phosphorylation, which was associated with inhibition of phosphorylation of the phosphatase and tensin homolog (PTEN). The ROCK1/PTEN pathway has been implicated in the neuronal hyperphosphorylation of tau that occurs in AD. To determine the function of ROCK1 in AD, brain tissue from 17 donors with low, intermediate or high probability of AD pathology were obtained and analyzed. Data showed that ROCK1 protein levels were reduced and ROCK1 colocalised with hyperphosphorylated tau in early neurofibrillary tangles. Intra-hippocampal delivery of a microRNA-146a specific inhibitor (antagomir) into 5xFAD mice showed enhanced hippocampal levels of ROCK1 protein and repressed tau hyperphosphorylation, partly restoring memory function in the 5xFAD mice. Our in vitro and in vivo results confirm that dysregulation of microRNA-146a biogenesis contributes to tau hyperphosphorylation and AD pathogenesis, and inhibition of this microRNA could be a viable novel in vivo therapy for AD.
刊物名称: SCIENTIFIC REPORTS
英文刊物名称: SCIENTIFIC REPORTS
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学科: Multidisciplinary Sciences
英文学科: Multidisciplinary Sciences
影响因子: 4.259
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论文类别: Article
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