|Comment by Sascha Weggen and Stefanie Hahn
To understand how presenilin mutations affect γ-secretase modulators (GSMs), it's worth elaborating on the differences in the studies by Hahn et al. (Hahn et al., 2011
) and Kretner et al. (Kretner et al., 2011
). Both studies used similar compounds. Both used E-2012 as an example of a potent non-acidic GSM without a carboxylic acid group. In addition, Kretner et al. used GSM-1 as a potent acidic GSM, whereas we used BB25, which is a close analogue of GSM-1 with similar potency. Kretner et al. concluded from their results that the attenuating effects of most presenilin mutations could be overcome by second-generation GSMs. In contrast, Hahn et al. concluded the opposite: that the efficacy of second-generation GSMs is reduced by presenilin mutations, in a similar fashion to what was previously reported by both of our groups for the less potent NSAID-type GSMs such as sulindac sulfide (Czirr et...