NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo

Abstract

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid protein (A42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid protein precursor (APP) transgenic mice, and plasma and brain levels of A and the drug were evaluated. These studies show that (a) eight FDA-approved NSAIDs lower A42 in vivo, (b) the ability of an NSAID to lower A42 levels in cell culture is highly predicative of its in vivo activity, (c) in vivo A42 lowering in mice occurs at drug levels achievable in humans, and (d) there is a significant correlation between A42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower A42 levels in broken cell -secretase assays, indicating that these compounds directly target the -secretase complex that generates A from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered A42 levels to the greatest extent. Because R-flurbiprofen reduces A42 levels by targeting -secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an A42 lowering agent.