title: FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo .
abstract: FLAP (5-lipoxygenase-activating protein) is a protein widely distributed within the central nervous system whose function is to regulate the activation of the 5-Lipoxygenase enzyme. Although previous works show that pharmacological blockade of FLAP improve the amyloidotic phenotype of the Tg2576, its contribution to tau pathology remains to be investigated. In the present paper, we studied the effect of FLAP pharmacological inhibition on the metabolism of endogenous tau in these mice. Total tau levels in the brains of mice receiving MK-591, a selective and specific FLAP inhibitor, were not changed when compared with controls. By contrast, treated animals had a significant reduction of tau phosphorylation at specific sites: Ser396; Ser396/Ser404; and Thr 231/Ser 235. This reduction was associated with a significant decrease in the activity of glycogen synthase kinase-3 beta, but not other kinases. In addition, MK-591-treated mice had a significant increase in the post-synaptic density protein-95 and the dendritic protein microtubule-associated protein 2. These data establish a novel functional role for FLAP in the metabolism of tau, and together with its known Aβ modulatory effect they suggest that its pharmacological inhibition could represent a novel therapeutic opportunity for Alzheimer's disease.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chu
authors.forename: E
authors.initials: E
authors.lastname: Lauretti
authors.forename: A
authors.initials: A
authors.lastname: Di Meco
authors.forename: D
authors.initials: D
authors.lastname: Praticò
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology*; D058927:5-Lipoxygenase-Activating Proteins / Q000187:drug effects* / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051528:Guanylate Kinases / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; C548593:Alox5ap protein, mouse; D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D007211:Indoles; C558298:Mapt protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D011804:Quinolines; D016875:tau Proteins; C078266:MK 0591; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D051528:Guanylate Kinases