Increasing evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) have beneficial effects in the treatment or prevention of Alzheimer's disease (AD). Although not proven, the presumed mechanisms are their anti-inflammatory and cyclo-oxygenase (COX) inhibitory properties. We recently observed the surprising finding that certain NSAIDs, at concentrations above that required for COX inhibition, caused a reduction in the levels of Abeta42 in medium of cultured cells. We subsequently obtained confirmation of the in vitro reduction in Abeta42 levels in brains of APP transgenic mice give a short course of NSAID, thereby demonstrating the physiological relevance of the findings from cultured cells in vivo. Accordingly, we hypothesize that this Abeta42 reducing activity of certain NSAIDs contributes to its potential benefits in AD, an effect that may well parallel the anti-inflammatory property of NSAIDs in general. However, the selectively activity against Abeta42 may be particularly important because Abeta42 is hypothesized to be the pathogenic and amyloidogenic species of amyloid beta-protein (Abeta), whose deposition in brain is believed to initiate the cascade of events that result in AD pathology. In preliminary studies, we observed that the reduction in Abeta42 is accompanied by an increase in Abeta38 species, suggesting that there has been a shift in protease activity rather than in absolute suppression of the Abeta42 gamma-secretase activity.
In Aims 1 and 2, we will examine the potential cellular pathways that mediate the reduction of Abeta42 levels by NSAIDs and determine how gamma- secretase activity has been perturbed. In the final Aim, we will define the role of COX inhibition on amyloid pathology in vivo. Ultimately, we wish to determine the pathways that mediate the selective lowering of Abeta42 by some NSAIDs. Definitive identification of the cellular target(s) will enable more selective drug development for the treatment of AD.
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