Blockade of PKC epsilon activation attenuates phorbol ester-induced increase of alpha-secretase-derived secreted form of amyloid precursor protein

The role of PKC epsilon in amyloid precursor protein (APP) processing was i nvestigated using APP-overexpressing B103 cells. As reported previously, a PKC activator, phorbol-12,13-dibutyrate (PDBu), enhanced secretion of APP a lpha, and this effect was blocked by a PKC inhibitor, GF109203X in this sys tem. Selective inhibition of PKC epsilon by overexpressing the PKC epsilon V1 region, which binds specifically to the receptor for activated C-kinase (RACK), blocked PDBu-induced enhancement of APP alpha secretion as well as PDBu-induced decrease in beta -secretase-derived APP C-terminal fragment pr oduction. On the other hand, the level of PKC epsilon, but not that of PKC alpha or PKC gamma, was substantially lower in the brains of Alzheimer's di sease patients compared to age-matched controls. These results add to a gro wing body of evidence that PKC epsilon plays an important role in modulatin g APP processing, and suggest that reduced PKC epsilon activity may contrib ute to the development of Alzheimer's disease. (C) 2001 Academic Press.