Since the discovery of the roles for NICDs and AICDs in gene transcription, the notion of c-secretase as a major player in pathologically altered gene transcription patterns has been steadily gaining ground with new substrates and their transcriptionally active ICDs being identified regularly. To investigate the impact of c-secretase activity on gene transcription, we compared two starkly contrasting situations: genetically engineered enhanced human csecretase activity and pharmacologically inhibited c-secretase activity in CHO cell lines. By investigating the effects of enhanced c-secretase activity on gene transcription using cDNA microarray analysis, we could show that the canonical, the planar cell polarity (PCP) and the Ca 2+ /Wnt pathways are transcriptionally affected through more than a dozen of Wnt signaling players (summarized in Fig. 6 ). From Proc and Wnt outside the membrane, through Frizzled and Dvl, to b-catenin and down to cell cycle regulating genes, the canonical Wnt pathway is the most affected of Wnt pathways. Several genes of the PCP Wnt pathway as well as Ca 2+ / Wnt pathways were found to be differentially expressed too (Fig. 6) . One of the cell cycle regulating genes is CYC-D, which itself is Figure 5 . Selected relative gene transcript levels in AD cortices. Real time PCR validated genes differentially transcribed in cells with enhanced c-secretase activity were selected and their gene transcript levels analyzed in ten to twelve AD and healthy human cortical brain tissue samples. Only the transcript levels of TERA, a gene of unknown function, is significantly altered with a two-fold increase in AD cortices. Note that TERA transcript levels were significantly reduced in cells with enhanced c-secretase activity (Fig. 3) . Relative quantification of gene transcription in CHO cells as well as in brain tissue used b-actin as housekeeping gene. Healthy control levels are displayed on the left part of each diagram, AD transcript levels on the right. Dashed lines indicate mean values for healthy controls (green) and AD cases (red). Double-headed arrows indicate tendencies of differences between groups. P2 values obtained from t-test are indicated in black boxes of the upper part of each diagram. doi:10.1371/journal.pone.0006952.g005 regulated by one of the most c-secretase-dependently altered genes reported by us, PTPRG.