One of the emerging approaches for the treatment of Alzheimer's disease aims at reducing toxic levels of Alphabeta-species through the modulation of secretases, namely by inducing alpha-secretase or inhibiting beta-secretase and/or gamma-secretase activities, or a combination of both. Although there is increasing evidence for the involvement of retinoids in Alzheimer's disease, their significance in the regulation of Alphabeta-peptide production remains unresolved. Our work concentrated on the regulation of all secretases mediated by all-trans-retinoic acid (ATRA), and supports the hypothesis that ATRA is capable of regulating them in an antiamyloidogenic sense at the levels of transcription, translation, and activation. Apart from increased alpha-secretase activity, we show a complex chain of regulatory events, resulting in impaired beta-secretase trafficking and membrane localization upon protein kinase C (PKC) activation by ATRA. Furthermore, ATRA demonstrates substrate specificity for beta-site amyloid precursor protein-cleaving enzyme (BACE) 1 over nonamyloidogenic BACE2 in beta-secretase regulation, which probably promotes competition for amyloid precursor protein between ADAM17 and BACE1. Additionally, we report enhanced secretion of soluble amyloid precursor protein alpha after ATRA exposure, possibly due to PKC activation, as pretreatment with the PKC inhibitor Gö6976 abolished all these events.