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  1. The new report by Page et al. describes important results that address the controversial issue of the mechanism of NSAID-type γ-secretase modulators (GSMs), particularly whether the compounds interact with enzyme or substrate to elicit their effects. Certain NSAIDs are well known to reduce production of Aβ42 while increasing Aβ38, and some (e.g., fenofibrate) have the opposite effect. Beher et al. (2004) reported that NSAIDs allosterically alter the γ-secretase active site on presenilin, while, in collaboration with Todd Golde and his lab, we reported that NSAIDs bind directly to APP substrate near the juxtamembrane region (Kukar et al., 2008). Page et al. now show that NSAIDs can alter Aβ production even when the APP substrate is mutated, demonstrating this effect both in APP-transfected cells and in purified enzyme assays. They first show that artificial and FAD mutations near the γ-secretase cleavage site do not prevent GSMs from exerting their effects. Thus, AD mouse models with such mutations may be more appropriate to study these GSMs, as aggressive FAD-mutant presenilins are insensitive to these compounds (Page et al., 2008; Czirr et al., 2008). Moreover, mutation of the putative NSAID binding region in APP apparently did not prevent the modulatory effects of NSAIDs, raising questions about whether this region is indeed an NSAID binding site. However, this finding is not necessarily inconsistent with GSMs targeting APP substrate in this region, as the mutants examined (G29A, A30I, and G33A; Aβ numbering) are relatively conservative (in contrast to the Kukar report, in which the 29-34 region of APP was swapped with the counterpart region of Notch). Thus, the conservative mutations in the present report may not necessarily interfere with NSAID binding. It is completely clear, however, that the proximal K28 is not involved in NSAID recognition by ionic interaction between the lysine amino group and the carboxylate of NSAIDs. Although this interaction has been hypothesized to be important, Page et al. show that K28E mutant APP substrate is quite responsive to NSAIDs in the cell-free assays and in a manner similar to wild-type APP.


    . Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism. J Biol Chem. 2004 Oct 15;279(42):43419-26. Epub 2004 Aug 10 PubMed.

    . Substrate-targeting gamma-secretase modulators. Nature. 2008 Jun 12;453(7197):925-9. PubMed.

    . Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem. 2008 Jan 11;283(2):677-83. PubMed.

    . Independent generation of Abeta42 and Abeta38 peptide species by gamma-secretase. J Biol Chem. 2008 Jun 20;283(25):17049-54. PubMed.

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