Protein kinase Calpha and beta1 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 neocortical microencephalopathy, increased protein kinase C (PKC) activity and altered processing of the amyloid precursor protein (APP) in neocortex of offspring. Here we show that PKCalpha and PKCbeta1 are the key regulators of alpha-secretory APP processing in guinea pig neocortex under these experimental conditions in vivo. This conclusion is based on the selective translocation of PKCalpha and PKCbeta1 isoforms to the cell membrane in MAM-treated guinea pigs, as revealed by Western blot analysis and by immunocytochemistry. Additionally, we observed that [3H]phorbol ester binding to protein kinase C increased by 38% and enhanced basal PKC activity by 58% in the neocortex of microencephalic guinea pigs. Inhibition of PKCalpha/PKCbeta1 by Gö6976 abolished this difference, suggesting that constitutive overactivation of these PKC isoforms accounts for the increase in total PKC activity. We also observed a strong positive correlation between levels of alpha-secretase-processed APP and PKC activity in the neocortex of individual animals, providing further evidence for a significant role of classical PKC isoforms in nonamyloidogenic APP processing.
Rossner
S
S
Department of Neurochemistry, Paul Flechsig Institute for Brain Research, Jahnallee 59, 04109 Leipzig, Germany. rossn@medizin.uni-leipzig.de
Mendla
K
K
Schliebs
R
R
Bigl
V
V
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D004789:Enzyme Activation / Q000502:physiology; D006168:Guinea Pigs; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000502:physiology*; D008746:Methylazoxymethanol Acetate / Q000494:pharmacology; D019579:Neocortex / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D007527:Isoenzymes; D011500:Protein Synthesis Inhibitors; D015240:Phorbol 12,13-Dibutyrate; D008746:Methylazoxymethanol Acetate; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D010447:Peptide Hydrolases