In order to see whether c-secretase affects the transcription of genes encoding interacting proteins, an interaction map of encoded proteins was generated with the string 8.0 data bank exclusively relying on evidence-based data. Clusters of protein interactions suggest the Wnt signaling pathways as a major focus of c-secretase-affected candidates (Fig. 4 , highlighted in grey). Indeed, we found several members of the canonical Wnt pathway, but also some interactors of the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway, to have c-secretase activity susceptible gene transcription (Fig. 4) . Some of these genes have been confirmed by real time PCR as well as DIGE experiments (Egger et al., unpublished). The largest decrease in gene transcription occurred for the gene encoding the protein Ptprg. This single-pass type I membrane protein dephosphorylates protein tyrosine phosphate and was recently suggested as a candidate tumor suppressor gene in nasopharyngeal carcinoma [39] . The same group reported functional evidence for a critical interaction of Ptprg with the extracellular matrix, which induces cell arrest, changes in cell cycle status and downregulation of cyclin D1 [39] . The latter is strongly affected by the canonical Wnt pathway. Ptprzeta and beta, structurally similar to Ptprg, interact with Psd95 [40] , which directly interacts with Wnt3a [41] . We could confirm that WNT3A transcripts show an increase of 2.8-fold (Fig. 3) . Further, Wnt3a has also been reported to interact directly with LRP1 ( Fig. 4, lower right) , a stimulator of the Wnt5a signaling pathway [42] and a known c-secretase substrate tying c-secretase to a major AD risk factor, ApoE [43] . Porcn, another protein that interacts with Wnt3a [44] , shows a three-fold increase in transcript level by the microarray experiment. Porcn also interacts with Wnt 6 (4-fold increase in microarray) as reported by the same group and is the first player of the canonical Wnt pathway as displayed by the Kegg database (mmu04310, http://www. genome.jp/dbget-bin/show_pathway?mmu04310). Wnt3a interacts with Frizzled 1 [45] , which showed a 5-fold increase in mRNA levels by our microarray. Following the canonical Wnt pathway, the first intracellular protein of the Wnt signaling cascade is ''Disheveled''. As confirmed by real time PCR, DVL3 mRNA is increased by 3-fold with enhanced c-secretase activity. Next, with the help of Gbp (microarray reports a 4-fold increase of Gbp2), Gsk-3b is inhibited, which in turn inhibits b-catenin. As made apparent by the graphical overview of interacting proteins encoded by genes we found to be transcriptionally susceptible to csecretase activity, b-catenin plays a central role, linking different proteins involved in different Wnt pathways (Fig. 4) . Furthermore, b-catenin has been found to function as a major node connecting PS1 and several proteins that are encoded by genes that we found to be differentially transcribed (Fig. 4) . b-catenin transcription was shown by the microarray to be 3-fold decreased. It interacts directly with cdh15 (which showed a 2.4-fold increase in transcript levels as confirmed by real time PCR, Fig. 3) , with Cdh1 (a known c-secretase substrate [46] ), with PS1 (the c-secretase catalytic subunit) and other proteins encoded by candidate genes reported by the microarray. In the context of the canonical Wnt pathway, b-catenin affects c-myc (CMYBP 3-fold increased on the microarray), c-jun (3-fold decreased on the microarray) and cyclin D (4-fold decreased on the microarray) -the latter, as mentioned, is also downregulated by Ptprg. Dvl3 however also interacts with other proteins encoded by candidate genes, among which Nkd1 is of special interest since it links the canonical with the planar cell polarity pathway where it has a different effect on Dvl. The Planar cell polarity pathway through several players, among them Rac (3fold decreased on the microarray) affects gene transcription, as we hypothesize for c-secretase activity changes. Through a chain of different mediators, the planar cell polarity Wnt pathway affects the cytoskeleton. Our microarray has reported some of these mediators to be differentially transcribed as c-secretase activity is enhanced; RhoA transcript levels for example are 3-fold decreased. Rock, which is known to directly interact with the csecretase substrate CD44 (CD44/Rho Family GTPase/ROCK2) [47, 48] , is transcriptionally affected too. Our top candidate UPP1 has only one interaction partner that was also reported to be differentially expressed by the microarray, the cytoskeleton protein vimentin (Vim) [35] . Vimentin itself is not new to AD research, as altered Vim distribution patterns were observed in FAD fibroblasts [36] . Also, UPP1 transcription is regulated by the transcription factor Oct3/4, as is the transcription of another candidate, called SPP1 [49] . Spp1 is a direct interaction partner of the aforementioned c-secretase substrate CD44 and strongly affects Ca 2+ levels [50] . It directly interacts with several proteins encoded by candidate genes, including PKCA, which itself directly interacts with Aplp2, a well-known c-secretase substrate, and Csnk2b, which directly interacts with b-catenin, thus closing the circle.