REVERSAL OF THE SWEDISH FAMILIAL ALZHEIMERS-DISEASE MUTANT PHENOTYPE IN CULTURED-CELLS TREATED WITH PHORBOL 12,13-DIBUTYRATE

Protein phosphorylation mediated by phorbol ester stimulates secretion of the beta-amyloid precursor protein (beta-APP) in cell culture. Thi s increase in secretion is produced by a transient increase in cleavag e to produce non-amyloidogenic protease nexin II products mediated by the alpha-secretase activity, and a concomitant decrease in beta-prote in production. Cells expressing the Swedish familial Alzheimer's disea se (FAD) variant of beta-APP produce more beta-protein and potentially amyloidogenic fragments than cells expressing wild-type protein; furt hermore, cleavage shifts from the alpha- to the beta-secretase cleavag e site of the precursor. We show that treatment with phorbol 12,13-dib utyrate (PDBu) of cells expressing the Swedish FAD reverses the mutant phenotype to wild-type. The alpha-secretase cleavage increases with a concomitant loss of beta-protein and other beta-secretase cleaved pro ducts. These results show that modulating beta-secretase cleavage dire ctly affects beta-protein production. It suggests that activating prot ein kinase C through, for example, muscarinic receptor agonists could reduce amyloidosis by modulating the level of beta-protein produced.