title: MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Neuroscience Research Australia &University of New South Wales, Randwick, 2031, New South Wales, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Yong-Fang
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Neuroscience Research Australia &University of New South Wales, Randwick, 2031, New South Wales, Australia.
authors.forename: Guinevere F
authors.initials: GF
authors.lastname: Lourenco
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Ru-Jing
authors.initials: RJ
authors.lastname: Ren
authors.affiliation: Neuroscience Research Australia &University of New South Wales, Randwick, 2031, New South Wales, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Department of Neurology &Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.|Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Sheng-Di
authors.initials: SD
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; C542542:MIRN146 microRNA, human; C558298:Mapt protein, mouse; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016875:tau Proteins; C515851:ROCK1 protein, human; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases