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PMID: 8415676 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 90 ·No. 19 ·1993-10-01 ·Pages 9195-8

Buxbaum JD, Koo EH, Greengard P

Abstract

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.

MeSH Terms
Amino Acid Sequence Amyloid beta-Peptides/antagonists & inhibitors,biosynthesis Animals CHO Cells Cricetinae Ethers, Cyclic/pharmacology Glioma Humans Kinetics Mutagenesis, Site-Directed Okadaic Acid Phorbol 12,13-Dibutyrate/pharmacology Phosphoprotein Phosphatases/antagonists & inhibitors Phosphorylation Protein Kinase C/metabolism Recombinant Proteins/antagonists & inhibitors,biosynthesis Transfection Tumor Cells, Cultured
Chemicals
Amyloid beta-Peptides Ethers, Cyclic Recombinant Proteins Okadaic Acid Phorbol 12,13-Dibutyrate Protein Kinase C Phosphoprotein Phosphatases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Buxbaum J D
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021.
Koo E H
Greengard P
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35 references, click to expand
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.90.19.9195
Published
1993-10-01
Pages
9195-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC47529
Subset
IM
Grants
NIA NIH HHS · AG07911 · United States
NIA NIH HHS · AG09464 · United States
NIA NIH HHS · AG10491 · United States
External Links
PubMed source DOI: 10.1073/pnas.90.19.9195 PMC Full Text View journal details
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