Although there is quite a substantial amount of data on the physiological role of N-terminal soluble ectodomains of APP -sAPPα and sAPPβ, for review see Chasseigneaux and Allinquant (2012) , the C-terminal products of APP proteolytic cleavage have only recently started to attract special attention. It is now rather well documented (although not without some controversy) that the C-terminal fragment of APP, AICD, can act as a transcription factor (Cao and Sudhof, 2001; Leissring et al., 2002; Schettini et al., 2010) . The controversy of the AICD research has been underpinned by utilization of different cell types expressing different APP isoforms and by the difficulties in detecting AICD due to its very short half life (Cupers et al., 2001) . However, it was repeatedly demonstrated that functional AICD, which translocates to the cell nucleus and up-regulates expression of a reporter NEP gene, is produced only via the amyloidogenic pathway and only from the APP 695 isoform (Goodger et al., 2009; Belyaev et al., 2010) . This process was also shown to be neuronal cell specific and lipid raft dependent (Belyaev et al., 2010) . In an earlier work by Cao and Sudhof (2001) , a yeast 2-hybrid (Y2H) screen was used to identify binding partners of the C-terminal domain of APP which revealed the role of Fe65 and the histone acetyltransferase (HAT) Tip60 in formation of functionally active AICD.