INCREASED SECRETION OF THE AMINO-TERMINAL FRAGMENT OF AMYLOID PRECURSOR PROTEIN IN BRAINS OF RATS WITH A CONSTITUTIVE UP-REGULATION OF PROTEIN-KINASE-C

Protein kinase C (PKC) activation stimulates release of secreted amylo id precursor protein (APP(s)) in several cell lines. To ascertain the role of PKC in regulating APP metabolism in vivo, we used an animal mo del (methylazoxymethanol-treated rats; MAM rats) in which PKC is perma nently hyperactivated in selected brain areas, i.e., cortex and hippoc ampus. A significant decrease in membrane-bound APP concentration was found in synaptosomes derived from cortex and hippocampus of MAM rats, where PKC is up-regulated, with a concomitant increase in APP(s) prod uction in soluble fractions of the same brain areas. In contrast, in a brain area not affected by MAM treatment (i.e., cerebellum), APP secr etion is similar in control and MAM rats, indicating that altered meta bolism of APP is restricted to only those areas in which the PKC syste m is up-regulated. In addition, phorbol esters or H-7 modulate APP(s) release in hippocampal slices from both control and MAM rats, further supporting an in vivo role for this enzyme in regulating metabolism of mature APP.