title: Pharmacologic inhibition of 5-lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy.
abstract: BACKGROUND
  5-Lipoxygenase (5-LO) is a protein widely distributed in the central nervous system where it modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer's disease. However, no data are available as to whether 5-LO is elevated in human tauopathy or if it directly influences tau pathology in a relevant model of the disease.
  
  
  METHODS
  We assayed 5-LO levels in brain samples from patients with tauopathy and transgenic tau mice, and we evaluated the effect of 5-LO pharmacologic inhibition on the phenotype of these mice.
  
  
  RESULTS
  The 5-LO protein is upregulated in human tauopathy and transgenic tau mice brains. Pharmacologic blockade of 5-LO in tau mice resulted in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism.
  
  
  CONCLUSIONS
  These results establish a key role of 5-LO in the development of the tau pathology phenotype and demonstrate it to be a novel viable therapeutic target for the pharmacologic treatment of human tauopathy.
authors: Center for Translational Medicine; Department of Pharmacology.
authors: Phillip F
authors: PF
authors: Giannopoulos
authors: Center for Translational Medicine; Department of Pharmacology.
authors: Jin
authors: J
authors: Chu
authors: Center for Substance Abuse Research.
authors: Margaret
authors: M
authors: Sperow
authors: Center for Translational Medicine; Department of Pharmacology.
authors: Jian-Guo
authors: JG
authors: Li
authors: Taub Institute for Alzheimer's Disease Research, Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors: W Haung
authors: WH
authors: Yu
authors: Center for Substance Abuse Research; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: Lynn G
authors: LG
authors: Kirby
authors: Center for Substance Abuse Research; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: Mary
authors: M
authors: Abood
authors: Center for Translational Medicine; Department of Pharmacology. Electronic address: praticod@temple.edu.
authors: Domenico
authors: D
authors: Praticò
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000201:enzymology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000201:enzymology* / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016859:Lipoxygenase Inhibitors; C054369:MAPT protein, human; D016875:tau Proteins; D001094:Arachidonate 5-Lipoxygenase; D051360:Cyclin-Dependent Kinase 5; C063449:zileuton; D006918:Hydroxyurea
keywords: 5-Lipoxygenase; Behavior; Frontotemporal dementia; Synapse; Tau protein; Tauopathy; Transgenic tau mice