Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β42 production by direct modulation of γ-secretase activity

Chronic use of nonsteroidal anti-inflammatory drugs ( NSAIDs) is associated with a lower risk of developing Alzheimer's disease. Recent evidence indicates that some NSAIDs specifically inhibit secretion of the amyloidogenic Abeta42 peptide in cultured cells and mouse models of Alzheimer's disease. The reduction of Abeta42 peptides is not mediated by inhibition of cyclooxygenases ( COX) but the molecular mechanism underlying this novel activity of NSAIDs has not been further defined. We now demonstrate that NSAIDs efficiently reduce the intracellular pool of Abeta42 in cell-based studies and selectively decrease Abeta42 production in a cell-free assay of gamma-secretase activity. Moreover, we find that presenilin-1 (PS1) mutations, which affect gamma-secretase activity, differentially modulate the cellular Abeta42 response to NSAID treatment. Overexpression of the PS1-M146L mutation enhances the cellular drug response to Abeta42 lowering NSAIDs as compared with cells expressing wildtype PS1. In contrast, expression of the PS1-DeltaExon9 mutation strongly diminishes the Abeta42 response, showing that PS1 mutations can modulate the cellular drug response to NSAID treatment both positively and negatively. Enhancement of the NSAID drug response was also observed with overexpression of the APP V717F mutation but not with Swedish mutant APP, which affects beta-secretase cleavage. In sum, these results strongly suggest that NSAIDs represent a founding group of compounds that lower Abeta42 production by direct modulation of gamma-secretase activity or its substrate.