Reversal of the Swedish familial Alzheimer's 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 the cell culture. This increase in secretion is produced by a transient increase in cleavage to produce non-amyloidogenic protease nexin II products mediated by the alpha-secretase activity, and a concomitant decrease in beta-protein production. Cells expressing the Swedish familial Alzheimer's disease (FAD) variant of beta-APP produce more beta-protein and potentially amyloidogenic fragments than cells expressing wild-type protein; furthermore, cleavage shifts from the alpha- to the beta-secretase cleavage site of the precursor. We show that treatment with phorbol 12,13-dibutyrate (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 products. These results show that modulating beta-secretase cleavage directly affects beta-protein production. It suggests that activating protein kinase C through, for example, muscarinic receptor agonists could reduce amyloidosis by modulating the level of beta-protein produced.
CNS - Department of Biophysics and Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492.
K M
KM
Felsenstein
K M
KM
Ingalls
L W
LW
Hunihan
S B
SB
Roberts
D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018680:Cholinergic Antagonists / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D009154:Mutation / Q000187:drug effects*; D010641:Phenotype; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D013548:Sweden
D016229:Amyloid beta-Peptides; D018680:Cholinergic Antagonists; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C