One of the emerging approaches for the treatment of Alzheimer’s disease aims at reducing toxic levels of Αβ-species through the modulation of secretases, namely by inducing α-secretase or inhibiting β-secretase and/or γ-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 Αβ-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 α-secretase activity, we show a complex chain of regulatory events, resulting in impaired β-secretase trafficking and membrane localization upon protein kinase C (PKC) activation by ATRA. Furthermore, ATRA demonstrates substrate specificity for β-site amyloid precursor protein-cleaving enzyme (BACE) 1 over nonamyloidogenic BACE2 in β-secretase regulation, which probably promotes competition for amyloid precursor protein between ADAM17 and BACE1. Additionally, we report enhanced secretion of soluble amyloid precursor protein α after ATRA exposure, possibly due to PKC activation, as pretreatment with the PKC inhibitor Gö6976 abolished all these events.