Proteolytic cleavage of the amyloid precursor protein (APP) by the successive actions of β- and γ-secretases generates several biologically active metabolites including the Alzheimer’s disease amyloid-β peptide (Aβ) and the APP intracellular domain (AICD), a 50-59 amino acid peptide. The latter, as we have demonstrated, regulates expression of the metallopeptidase neprilysin (NEP) which, in turn, degrades the Aβ peptide. This up-regulation of NEP requires binding of the AICD peptide to the NEP promoter while down-regulation of NEP gene involves histone deacetylase occupancy at the promoter site. Functionally active AICD was found to be preferentially generated from the amyloidogenic processing of the neuronal APP695 isoform. We have examined whether differences exist between the various APP isoforms in the production of AICD and have recently confirmed that AICD action is modulated via MED12, a subunit of the RNA polymerase II transcriptional Mediator complex. Since AICD is rapidly degraded in the cell and seldom detected we have developed several techniques to manipulate AICD peptide levels in order to study its function and established that γ-secretase inhibitors and hypoxic conditions reduce AICD levels, whereas the tyrosine kinase inhibitor, Gleevec, and alkalization with ammonium chloride increase AICD levels in the cells. We have shown that in SH-SY5Y-APP695 cells expression of several other genes is also changed. However, unlike NEP, AICD appeared to down-regulate expression of the EGFR gene. Chromatin immunoprecipitation experiments also confirmed the presence of AICD on the promoter region of the transthyretin (TTR) gene in APP695 over-expressing cells. Like NEP, TTR is also involved in Aβ peptide clearance from the brain. This study clearly demonstrates an important role of APP and AICD in epigenetic regulation of various neuronal genes and especially of those participating in peptide metabolism and clearance. Supported by MRC, ARUK, Programme of RAS “Fundamental Sciences to Medicine”, RFBR 13-04-00388.