Protein kinase C alpha and beta 1 isoforms are regulators of alpha-secretory proteolytic processing of amyloid precursor protein in vivo

We have recently shown that in utero treatment of guinea pigs with the DNA methylating substance methylazoxymethanol acetate (MAM) results in neocorti cal microencephalopathy, increased protein kinase C (PKC) activity and alte red processing of the amyloid precursor protein (APP) in neocortex of offsp ring. Here we show that PKC alpha and PKC beta1 are the key regulators of a lpha -secretory APP processing in guinea pig neocortex under these experime ntal conditions in vivo. This conclusion is based on the selective transloc ation of PKC alpha and PKC beta1 isoforms to the cell membrane in MAM-treat ed guinea pigs, as revealed by Western blot analysis and by immunocytochemi stry. Additionally, we observed that [H-3]phorbol ester binding to protein kinase C increased by 38% and enhanced basal PKC activity by 58% in the neo cortex of microencephalic guinea pigs. Inhibition of PKC alpha /PKC beta1 b y Go6976 abolished this difference, suggesting that constitutive overactiva tion of these PKC isoforms accounts for the increase in total PKC activity. We also observed a strong positive correlation between levels of alpha -se cretase-processed APP and PKC activity in the neocortex of individual anima ls, providing further evidence for a significant role of classical PKC isof orms in nonamyloidogenic APP processing.