title: 5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer's disease.
abstract: BACKGROUND
  5-lipoxygenase activating protein (FLAP) is abundantly present in the central nervous system. Although its function has been extensively interrogated in the context of peripheral inflammation, novel roles for this protein are emerging in the central nervous system. The objective of our study was to investigate the functional role that FLAP plays in a mouse model of Alzheimer's disease (AD) with plaques and tangles (i.e., 3xTg mice).
  
  
  METHODS
  By implementing a genetic knockout of FLAP and pharmacologic inhibition with a FLAP inhibitor (MK-591), we evaluated the effect on the AD-like neuropathology, cognition, and synaptic plasticity in the 3xTg mice.
  
  
  RESULTS
  We show that reduction of FLAP leads to amelioration of cognition and memory along with the rescuing of synaptic dysfunction at an early age before the development of overt neuropathology. Genetic knockout and pharmacologic inhibition of FLAP also yielded an improvement in AD pathology through a reduction in Aβ via the γ-secretase pathway and a decrease in tau phosphorylation through the cdk5 pathway.
  
  
  CONCLUSIONS
  Our studies identify a novel functional role for FLAP in regulating memory and synaptic plasticity. They establish this protein at the crossroad of multiple pathways that ultimately contribute to the development of the entire AD-like phenotype, making it a viable therapeutic target with disease-modifying capacity for the treatment of this disease.
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Giannopoulos
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.forename: Yash B
authors.initials: YB
authors.lastname: Joshi
authors.forename: Margaret
authors.initials: M
authors.lastname: Sperow
authors.forename: Jin-Guo
authors.initials: JG
authors.lastname: Li
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Kirby
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology; D058927:5-Lipoxygenase-Activating Proteins / Q000187:drug effects / Q000502:physiology*; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008297:Male; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011804:Quinolines / Q000494:pharmacology; D013569:Synapses / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D016229:Amyloid beta-Peptides; D007211:Indoles; D011804:Quinolines; D016875:tau Proteins; C078266:MK 0591
keywords: Alzheimer’s disease; Amyloid beta; FLAP protein; behavior; tau protein; transgenic mouse models