Constitutive overactivation of protein kinase C in guinea pig brain increases alpha-secretory APP processing without decreasing beta-amyloid generation

Whilst if is generally accepted that the activation of protein kinase C (PK C) increases amyloid precursor protein (APP) secretion in vitro, the role o f PKC in the regulation of APP processing and beta-amyloid generation in vi vo is still not well understood. In order to address this question, we esta blished the animal model of neocortical microencephalopathy in guinea pigs caused by in utero treatment with methylazoxymethanol acetate, a DNA-methyl ating substance that eliminates proliferating cells of neuroepithelial orig in. The induction of this neocortical malformation is accompanied by consti tutive overactivation of PKC in the neocortex of the offspring. In the cort ical and hippocampal tissues of juvenile microencephalic guinea pigs (postn atal day 30), we observed significant increases in basal (by 58% and 74%, r espectively,) and phorbol ester-stimulated PKC enzyme activity (by 47% and 71%) as compared to age-matched control animals. in the same cortical/hippo campal preparations of methylazoxymethanol-treated animals, there was incre ased alpha-secretion of APP by 35% and 30% as measured by Western blot anal ysis using the antibody 6E10, whilst total APP secretion as well as APP mRN A expression remained unaltered. This upregulation of APP alpha-secretion w as limited to brain areas that displayed elevated PKC activity. However, co nstitutive overactivation of neocortical PKC did not affect the generation of beta-amyloid peptides 1-40 or 1-42 as measured by ELISA, suggesting that only the alpha-secretase pathway of APP processing is affected by chronic PKC overactivation in vivo.