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

Abstract

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 Aβ42 peptide in cultured cells and mouse models of Alzheimer's disease. The reduction of Aβ42 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 Aβ42 in cell-based studies and selectively decrease Aβ42 production in a cell-free assay of y-secretase activity. Moreover, we find that presenilin-1 (PS1) mutations, which affect γ-secretase activity, differentially modulate the cellular Aβ42 response to NSAID treatment. Overexpression of the PS1-M146L mutation enhances the cellular drug response to Aβ42 lowering NSAIDs as compared with cells expressing wild-type PS1. In contrast, expression of the PS1-ΔExon9 mutation strongly diminishes the Aβ42 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 β-secretase cleavage. In sum, these results strongly suggest that NSAIDs represent a founding group of compounds that lower Aβ42 production by direct modulation of γ-secretase activity or its substrate.