title: Morroniside-Induced PP2A Activation Antagonizes Tau Hyperphosphorylation in a Cellular Model of Neurodegeneration.
abstract: BACKGROUND
  An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD.
  
  
  OBJECTIVE
  To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A.
  
  
  METHODS
  SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h. PP2Ac siRNA was transfected into HEK293 cells to determine the direct interaction of MOR with PP2A. Western blotting was used to measure the expression of proteins and enzymes. PP2A activity was measured by molybdenum blue spectrophotometry.
  
  
  RESULTS
  Pretreatment with MOR improved the cellular morphological damage and inhibited tau hyperphosphorylation in SK-N-SH cells induced by OA, a PP2A inhibitor. Moreover, MOR increased PP2A activity, concurrent with a decrease in the expression of demethylated PP2A at Leu309 and phosphorylated PP2A at Tyr307. MOR decreased protein phosphatase methylesterase 1 (PME-1) expression and the ratio of PME-1/leucine carboxyl methyltransferase 1 (LCMT-1). Furthermore, MOR treatment decreased the phosphorylation of Src at Tyr416, which regulates the phosphorylation of PP2A. MOR had no effect on PP2Ac expression and tau hyperphosphorylation in PP2Ac siRNA-transfected cells.
  
  
  CONCLUSIONS
  MOR attenuated OA-induced tau hyperphosphorylation via PP2A activation, and its mechanism might be related to the regulation of PP2Ac post-translational modification and upstream enzymes such as Src and PME-1.
authors.affiliation: Department of Pharmacology, Xuanwu Hospital of Capital Medical University; Beijing Institute for Brain disorder; Beijing Engineering Research Center for Nerve System Drugs; Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China.
authors.forename: Cui-cui
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Xuanwu Hospital of Capital Medical University; Beijing Institute for Brain disorder; Beijing Engineering Research Center for Nerve System Drugs; Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China.|First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Xue-xian
authors.initials: XX
authors.lastname: Kuai
authors.affiliation: Department of Pharmacology, Xuanwu Hospital of Capital Medical University; Beijing Institute for Brain disorder; Beijing Engineering Research Center for Nerve System Drugs; Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China.|Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China.
authors.forename: Wen-bin
authors.initials: WB
authors.lastname: Gao
authors.affiliation: First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Jian-chun
authors.initials: JC
authors.lastname: Yu
authors.affiliation: Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Xuanwu Hospital of Capital Medical University; Beijing Institute for Brain disorder; Beijing Engineering Research Center for Nerve System Drugs; Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Xuanwu Hospital of Capital Medical University; Beijing Institute for Brain disorder; Beijing Engineering Research Center for Nerve System Drugs; Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006027:Glycosides / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D006027:Glycosides; D034741:RNA, Small Interfering; C488401:morroniside; D016875:tau Proteins; D019319:Okadaic Acid; D014443:Tyrosine; D000071679:Glycogen Synthase Kinase 3 beta; D054648:Protein Phosphatase 2
keywords: Alzheimer’s disease; morroniside; okadaic acid; protein phosphatase-2A; tau hyperphosphorylation