Insensitivity to Aβ42-lowering nonsteroidal anti-inflammatory drugs and γ-secretase inhibitors is common among aggressive presenilin-1 mutations

Abstract

Aβ42-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) constitute the founding members of a new class of γ-secretase modulators that avoid side effects of pan-γ-secretase inhibitors on NOTCH processing and function, holding promise as potential disease-modifying agents for Alzheimer disease (AD). These modulators are active in cell-free γ-secretase assays indicating that they directly target the γ-secretase complex. Additional support for this hypothesis was provided by the observation that certain mutations in presenilin-1 (PS1) associated with early-onset familial AD (FAD) change the cellular drug response to Aβ42-lowering NSAIDs. Of particular interest is the PS1-ΔExon9 mutation, which provokes a pathogenic increase in the Aβ42/Aβ40 ratio and dramatically reduces the cellular response to the Aβ42-lowering NSAID sulindac sulfide. This FAD PS1 mutant is unusual as a splice-site mutation results in deletion of amino acids Thr 291-Ser319 including the endoproteolytic cleavage site of PS1, and an additional amino acid exchange (S290C) at the exon 8/10 splice junction. By genetic dissection of the PS1-ΔExon9 mutation, we now demonstrate that a synergistic effect of the S290C mutation and the lack of endoproteolytic cleavage is sufficient to elevate the Aβ42/Aβ40 ratio and that the attenuated response to sulindac sulfide results partially from the deficiency in endoproteolysis. Importantly, a wider screen revealed that a diminished response to Aβ42-lowering NSAIDs is common among aggressive FAD PS1 mutations. Surprisingly, these mutations were also partially unresponsive to γ-secretase inhibitors of different structural classes. This was confirmed in a mouse model with transgenic expression of the PS1-L166P mutation, in which the potent γ-secretase inhibitor LY-411575 failed to reduce brain levels of soluble Aβ42. In summary, these findings highlight the importance of genetic background in drug discovery efforts aimed at γ-secretase, suggesting that certain AD mouse models harboring aggressive PS mutations may not be informative in assessing in vivo effects of γ-secretase modulators and inhibitors. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.