FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo?

摘要

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.