O2‐05‐03: FLAP involvement in the amyloidotic phenotype of an Alzheimer's disease transgenic mouse model

Abstract

The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system whose activity is regulated by the presence and availability of another protein called 5LO-activating protein or FLAP. While previous works show that 5LO is involved in Alzheimer's disease (AD) pathogenesis, no data are available on the role that FLAP plays in AD. In the present paper, we studied the in vivo effect of FLAP pharmacologic inhibition with a selective inhibitor of this protein, MK-591, on the amyloidotic phenotype of the Tg2576 mice. Aß deposition in the brains of mice receiving MK-591, a selective and specific FLAP inhibitor, was significantly reduced when compared with controls. This reduction was associated with a similar decrease in brain Aß peptides levels. MK-591 treatment did not induce any change in the steady state levels of amyloid-b precursor protein (APP), BACE-1 or ADAM-10. By contrast, it resulted in a significant reduction of PS1, nicastrin, Pen-2 and APH-1, the four components of the g-secretase complex, at the protein and message level. Furthermore, in vitro studies confirmed that MK-591 prevents Aβ formation by modulating g-secretase complex levels without affecting Notch signaling. These data establish a novel functional role for FLAP in the pathogenesis of AD-like amyloidosis, and suggest that its pharmacological inhibition could provide a novel therapeutic opportunity for AD.