title: Conditional inactivation of Akt three isoforms causes tau hyperphosphorylation in the brain.
abstract: BACKGROUND
  Tau hyperphosphorylation plays a critical role in neurodegenerative diseases [EMBO Mol Med. 6:1142-60, 2014; Annu Rev Neurosci. 24:1121-59, 2001]. Recent evidence has shown that Akt is down-regulated in AD [J Pathol. 225:54-62, 2011]. However, it remained unknown which pathological process, e.g. tau pathology or neuron death, Akt may contribute to. In this study, Cre-loxP technique was employed to generate a viable Akt three isoforms conditional knockout (Akt cTKO) mouse in which total Akt levels were dramatically reduced in the adult brain.
  
  
  RESULTS
  Significantly increased levels of tau phosphorylated (p-tau) at various sites were observed in Akt cTKO mice as compared to age-matched littermate controls. Increased levels for phosphorylated GSK3α and phosphorylated PKA substrates were detected in Akt cTKO brains. In contrast, no significant changes on p-tau levels were found in Akt1(-/-), Akt2(-/-) or Akt3(-/-) mice.
  
  
  CONCLUSIONS
  Akt may regulate tau phosphorylation in the adult brain by affecting activities for PKA and GSK3α.
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Geriatric, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Avenue, Nanjing, Jiangsu Province, 210008, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China.
authors.forename: Congyu
authors.initials: C
authors.lastname: Xu
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Lu
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China.
authors.forename: Jinxing
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Geriatric, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Avenue, Nanjing, Jiangsu Province, 210008, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Neurology, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Avenue, Nanjing, Jiangsu Province, 210008, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zou
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Xuanwu District, Beijing, 100050, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Neurology, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Avenue, Nanjing, Jiangsu Province, 210008, China. xuyun20042001@aliyun.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China. yangzz@nicemice.cn.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China. chenguiquan@nju.edu.cn.
authors.forename: Guiquan
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003433:Crosses, Genetic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C558298:Mapt protein, mouse; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D016875:tau Proteins; D013629:Tamoxifen; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha