A peculiar aspect of the FLAP 5LO pathway is the fact that its expression levels are significantly increased in the CNS with aging, and that this increase is also region specific since selleck chemicals Y-27632 it mainly manifests in the hippocampus, an area vulnerable to neurodegenerative insults. Interestingly, recent studies showed that hippocampi from patients with Alzheimers disease have higher 5LO immunoreactivity when compared with healthy controls, and that the genetic absence of 5LO Inhibitors,Modulators,Libraries results in a significant reduction of the brain amyloidotic phenotype of amyloid B precursor protein transgenic mice. Inhibitors,Modulators,Libraries Taken together, these data suggest an involvement of this pathway in AD pathogenesis, and support the hypothesis that it plays a functional role in AD development.

However, no studies are available testing the specific and direct role that FLAP may also play in the development of the AD like amyloidotic phenotype of the Tg2576 mice. To this end, in the current study Inhibitors,Modulators,Libraries we chronically admi nistered these mice with a selective and specific orally available inhibitor of FLAP activation, MK 591. At the end of the study, compared with mice receiving vehicle, the group treated with MK 591 showed a signifi cant reduction in the amount of amyloid B peptide formed and deposited in their brains. These changes were not associated with any significant modification of total APP, B site amyloid precursor protein cleaving enzyme 1 or disintegrin and metalloproteinase domain containing protein 10 protein levels. By contrast, we observed that the group adminis tered with MK 591 had a significant reduction of the secretase complex at the protein and message level.

These results were further confirmed in vitro using neur onal cells stably expressing the Inhibitors,Modulators,Libraries human APP Swedish mu tant, neuro 2 A neuroblastoma APPswe cells. Methods Mice and treatments All animal procedures were approved by the Institutional Animal Care and Usage Committee and in accordance with the National Institute of Health guidelines. The Tg2576 transgenic mice expressing human APP with the Swedish mutation used in these studies were as previously described. They were genotyped by PCR analysis using tail DNA and kept in a pathogen free envir onment, on a 12 hour lightdark cycle and had access to food and water ad libitum. All the experiments presented in this paper were performed with female mice.

Starting at 7 months of age, mice were randomized to receive MK 591 or vehicle in their chow diet for 8 months until they were 15 months old. Consider ing that each mouse eats Inhibitors,Modulators,Libraries on average 5 gday of chow diet and the diet is formulated for 320 mg MK 591 per kg diet, the final dose of the active drug was approximately 40 mgkg weightday. During the study, mice in both groups gained weight regularly, and no signifi cant difference in weight was detected between the two groups. No macroscopic effect on the overall general health protein inhibitor was observed in the animals receiving the active treatment.