Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide.
The major component of amyloid plaque cores and cerebrovascular amyloid deposits found in Alzheimer disease is the beta/A4 peptide, which is derived from the Alzheimer amyloid protein precursor (APP). Recent evidence suggests that abnormalities in beta/A4 peptide production or beta/A4 peptide aggregation may underlie cerebral amyloidosis. In the present study, treatment of cells with phorbol dibutyrate, which activates protein kinase C, and/or okadaic acid, which inhibits protein phosphatases 1 and 2A, reduced beta/A4 peptide production by 50-80%. These effects were observed with APP695 and APP751 expressed in stably transfected CHO cells, as well as with endogenous APP in human glioma (Hs 683) cells. Phorbol dibutyrate also decreased beta/A4 peptide production in cells expressing various mutant forms of APP associated with familial Alzheimer disease, one of which was reported to manifest greatly increased beta/A4 peptide production in cultured cells. Mastoparan and mastoparan X, compounds which can activate phospholipase C and hence protein kinase C, also decreased beta/A4 peptide production in CHO cells stably transfected with APP695. A model is presented in which decreases in beta/A4 peptide production can be achieved by accelerating the metabolism of APP through a nonamyloidgenic secretory pathway.
Buxbaum
J D
JD
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021.
Koo
E H
EH
Greengard
P
P
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005910:Glioma; D006801:Humans; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D019319:Okadaic Acid; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D004988:Ethers, Cyclic; D011994:Recombinant Proteins; D019319:Okadaic Acid; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases