This suggests translational regulation of the genes codifying for the secretase complex. Different potential transcriptional factor binding sites have been reported within the promoter regions of these genes. Among them, a CREB binding site has been shown to be essential for APH 1, Pen 2 and PS1 tran scriptional regulation. In our studies we the found that, compared with the vehicle group, mice receiving Inhibitors,Modulators,Libraries MK 591 had a significant reduction in the levels of this transcription factor. By contrast, no difference between the two groups was observed when levels of Sp1, a tran scription factor known to be involved in the regulation of the B secretase 1 mRNA, were assayed, suggest ing a specific effect on CREB.

Taken together, these findings support the hypothesis that FLAP pharmacological blockade by preventing 5LO activation modulates CREB levels and results in reduced Inhibitors,Modulators,Libraries transcription of the mRNAs for the secretase complex, which ultimately is responsible for the reduction in AB formation in vivo. AB is a major component of the hallmark AD brain lesions, and is generated from the sequential proteolytic processing of APP by the enzymes B and secretase. The necessary role of secretase in the pathogen esis of AD makes it a major target for drug development, with an effort focused on the ability to inhibit this com plex. However, a key factor in establishing the clinical validity of secretase inhibitors is the demonstration of a differential effect between APP processing and alterna tive substrates of this secretase, particularly the Inhibitors,Modulators,Libraries Notch signaling.

Here, we demonstrate that the MK 591 effect on the secretase complex is completely independent of any effect on the Notch signaling pathway. This in vitro observation is further supported by the fact that, during the study and at the end of the chronic treatment, animals receiving the active drug did not have any macroscopic difference in organs that Inhibitors,Modulators,Libraries are typical Notch targets. The novel biological effect of the drug used in the current study is in agreement with previous studies and in line with a modulator activity of this drug on the secretase. It supports the novel idea that it is possible Inhibitors,Modulators,Libraries to develop secretase modulators that alter AB formation while preserving other important functions of the com plex. This observation makes any potential thera peutic application of FLAP inhibitor, which could act as secretase modulators, in AD feasible without the potential toxicity of the classical inhibitors of the com plex.

Conclusions Our studies establish FLAP as a novel therapeutic target for AD like amyloidosis. They represent the successful completion of the initial step for pre clinical development of inhibitors of this protein as potential novel disease modifying agents for AD. Introduction Activated glial cells secrete a variety of proteins includ ing proinflammatory cytokines, chemokines, sellckchem and neuro toxic factors under inflammatory or pathological conditions.