Importantly, we found several key players of the three Wnt pathways to be transcriptionally altered in response to enhanced csecretase. We confirmed one of these, Wnt3a, to be increased by 2.8-fold in S-1 cells (Fig. 3 ). Aoyama et al. have reported that Wnt3a can influence Notch protein levels and increase Notch1 activation [37] , which increases the effect of enhanced c-secretase even further through substrate enhancement. Thus, enhanced csecretase activity may lead to increased WNT3A transcription, which in turn can increase the protein levels of the NICD-carrying c-secretase substrate. This proposed enhancement of the canonical Wnt pathway is further supported by the recent observation that b-catenin (the central protein that also ties PS1 to the pathway) modulates the level and transcriptional activity of Notch1/NICD through their direct interaction [38] . Several proteins, including Frizzled and Disheveled (Dvl), relay the Wnt signal along the canonical pathway between Wnt and b-catenin. We found that they both show increased gene transcription in our microarray analysis. DVL3 was confirmed by qPCR to increase in mRNA copy numbers by 3-fold (Fig. 3) . Taken together with the microarray data showing differential transcription of PROC, DKK, LRP5/6, GBP, AXIN, b-catenin, C-JUN and CYC D (all part of the canonical Wnt pathway-for further details see 'Discussion'), our data suggest a strong transcriptional effect on this pathway by c-secretase activity and resulting alterations in gene expression. CYC D has also been reported to be downregulated by Protein tyrosine phosphatase receptor type G (PTPRG) [39] . We confirmed by real time PCR that PTPRG transcript level is reduced by 515-fold (Fig. 3) . AMN1 (levels down 978-fold) has also been connected with cell cycle regulation in yeast, but its role in mammals is not well known. TERA, a gene of unknown function (levels down 24-fold), has also been associated with Wnt antagonism (see Fig. 3 and results of human cortex analysis). b-actin served as housekeeping gene.