Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation.
The turnover and processing of the Alzheimer beta/A4 amyloid precursor protein (beta APP) has been studied in PC12 cells after treatment with agents that regulate protein phosphorylation. Phorbol 12,13-dibutyrate, an agent that stimulates protein kinase C, decreased the levels of mature beta APP and increased the levels of 15- and 19-kDa peptides. These peptides appeared to be COOH-terminal fragments of beta APP, which arose when phorbol 12,13-dibutyrate increased the rate of proteolytic processing of mature forms of beta APP. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, also led to decreased levels of mature beta APP and increased levels of the 15- and 19-kDa peptides. H-7, an inhibitor of protein kinase C and of several other protein kinases, apparently decreased the rate of proteolytic processing of mature beta APP. The sizes of the putative COOH-terminal fragments observed after treatment with either phorbol 12,13-dibutyrate or okadaic acid suggest that one or both may contain the entire beta/A4 region of beta APP and thus be amyloidogenic. Our results support the hypothesis that abnormal protein phosphorylation may play a role in the development of the cerebral amyloidosis that accompanies Alzheimer disease.
Buxbaum
J D
JD
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021.
Gandy
S E
SE
Cicchetti
P
P
Ehrlich
M E
ME
Czernik
A J
AJ
Fracasso
R P
RP
Ramabhadran
T V
TV
Unterbeck
A J
AJ
Greengard
P
P
D000310:Adrenal Gland Neoplasms; D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D002460:Cell Line; D004988:Ethers, Cyclic / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008715:Methionine / Q000378:metabolism; D008970:Molecular Weight; D019319:Okadaic Acid; D010673:Pheochromocytoma; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D011499:Protein Processing, Post-Translational; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014158:Transcription, Genetic
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D004988:Ethers, Cyclic; D011498:Protein Precursors; D019319:Okadaic Acid; D015240:Phorbol 12,13-Dibutyrate; D008715:Methionine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate