NSAID-Based γ-Secretase Modulators Do Not Bind to the Amyloid-β Polypeptide

gamma-Secretase modulators (GSMs) have received much attention as potential therapeutic agents for Alzheimer's disease (AD). GSMs increase the ratio between short and long forms of the amyloid-beta (A beta) polypeptides produced by gamma-secretase and thereby decrease the amount of the toxic amyloid species. However, the mechanism of action of these agents is still poorly understood. One recent paper [Richter et al. (2010) Proc. Natl. Acad. Sci. U. S. A. 107, 14597-14602] presented data that were interpreted to support direct binding of the GSM sulindac sulfide to A beta(42), supporting the notion that GSM action is linked to direct binding of these compounds to the A beta domain of its immediate precursor, the 99-residue C-terminal domain of the amyloid precursor protein (C99, also known as the beta-CTF). Here, contrasting results are presented that indicate there is no interaction between monomeric sulindac sulfide and monomeric forms of A beta 42. Instead, it was observed that sulindac sulfide is itself prone to form aggregates that can bind nonspecifically to A beta 42 and trigger its aggregation. This observation, combined with data from previous work [Beel et al. (2009) Biochemistry 48, 11837-11839], suggests both that the poor behavior of some NSAID-based GSMs in solution may obscure results of binding assays and that NSAID-based GSMs do not function by directly targeting C99. It was also observed that another GSM, flurbiprofen, fails to bind to monomeric A beta 42 or to C99 reconstituted into bilayered lipid vesicles. These results disfavor the hypothesis that these NSAID-based GSMs exert their modulatory effect by directly targeting a site located in the A beta 42 domain of free C99.