Blockade of PKCϵ Activation Attenuates Phorbol Ester-Induced Increase of α-Secretase-Derived Secreted Form of Amyloid Precursor Protein

Abstract

The role of PKCϵ in amyloid precursor protein (APP) processing was investigated using APP-overexpressing B103 cells. As reported previously, a PKC activator, phorbol-12,13-dibutyrate (PDBu), enhanced secretion of APPα, and this effect was blocked by a PKC inhibitor, GF109203X in this system. Selective inhibition of PKCϵ by overexpressing the PKCϵ V1 region, which binds specifically to the receptor for activated C-kinase (RACK), blocked PDBu-induced enhancement of APPα secretion as well as PDBu-induced decrease in β-secretase-derived APP C-terminal fragment production. On the other hand, the level of PKCϵ, but not that of PKCα or PKCγ, was substantially lower in the brains of Alzheimer's disease patients compared to age-matched controls. These results add to a growing body of evidence that PKCϵ plays an important role in modulating APP processing, and suggest that reduced PKCϵ activity may contribute to the development of Alzheimer's disease.