A␤42-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) constitute the founding members of a new class of ␥-secretase modulators that avoid side effects of pan-␥-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 ␥-secretase assays indicating that they directly target the ␥-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 A␤42-lowering NSAIDs. Of particular interest is the PS1-⌬Exon9 mutation, which provokes a pathogenic increase in the A␤42/A␤40 ratio and dramatically reduces the cellular response to the A␤42-lowering NSAID sulindac sulfide. This FAD PS1 mutant is unusual as a splice-site mutation results in deletion of amino acids Thr 291 -Ser 319 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-⌬Exon9 mutation, we now demonstrate that a synergistic effect of the S290C mutation and the lack of endoproteolytic cleavage is sufficient to elevate the A␤42/A␤40 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 A␤42-lowering NSAIDs is common among aggressive FAD PS1 mutations. Surprisingly, these mutations were also partially unresponsive to ␥-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 ␥-secretase inhibitor LY-411575 failed to reduce brain levels of soluble A␤42. In summary, these findings highlight the importance of genetic background in drug discovery efforts aimed at ␥-secretase, suggesting that certain AD mouse models harboring aggressive PS mutations may not be informative in assessing in vivo effects of ␥-secretase modulators and inhibitors.

Pramipexole has been shown to possess neuroprotective properties in vitro that are partly independent of its dopaminergic agonism. The site of neuroprotective action is still unknown. Using [3 H]pramipexole, we show that the drug enters and accumulates in cells and mitochondria. Detoxification of reactive oxygen species (ROS) by pramipexole is shown in vitro and in vivo by evaluating mitochondrial ROS release and aconitase-2 activity, respectively. Pramipexole and its (ϩ)-enantiomer

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