Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer's disease mouse model

Background: the 5-lipoxygenase enzyme is widely distributed within the central nervous system and its activity is regulated by the presence and availability of another protein,called 5-lipoxygenase activating protein. while previous works have shown that 5-lipoxygenase is involved in the pathogenesis of alzheimer's disease,no data are available on the role that 5-lipoxygenase activating protein plays in alzheimer's disease.methods: in the present paper,we studied the effect of pharmacologic inhibition of 5-lipoxygenase activating protein on the amyloidotic phenotype of tg2576 mice.results: amyloid β peptide (aβ) deposition in the brains of mice receiving mk-591,a selective and specific 5-lipoxygenase activating protein inhibitor,was significantly reduced when compared with controls. this reduction was associated with a similar decrease in brain aβ peptides levels. mk-591 treatment did not induce any change in the steady-state levels of amyloid-β precursor protein,β-site amyloid precursor protein cleaving enzyme 1 or disintegrin and metalloproteinase domain-containing protein 10. by contrast,it resulted in a significant reduction of the γ-secretase complex,at the protein and message level. furthermore,in vitro studies confirmed that mk-591 prevents aβ formation by modulating γ-secretase complex levels without affecting notch signaling.conclusions: these data establish a novel functional role for 5-lipoxygenase activating protein in the pathogenesis of alzheimer's disease-like amyloidosis,and suggest that its pharmacological inhibition could provide a novel therapeutic opportunity for alzheimer's disease. © 2012 chu and praticò; licensee biomed central ltd.