Protein phosphorylation inhibits production of Alzheimer amyloid β/A4 peptide

Joseph D. Buxbaum, Edward H. Koo, Paul Greengard

Research output: Contribution to journalArticlepeer-review

273 Scopus citations


The major component of amyloid plaque cores and cerebrovascular amyloid deposits found in Alzheimer disease is the β/A4 peptide, which is derived from the Alzheimer amyloid protein precursor (APP). Recent evidence suggests that abnormalities in β/A4 peptide production or β/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 β/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 β/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 β/ A4 peptide production in cultured cells. Mastoparan and mastoparan X, compounds which can activate phospholipase C and hence protein kinase C, also decreased β/ A4 peptide production in CHO cells stably transfected with APP695. A model is presented in which decreases in β/A4 peptide production can be achieved by accelerating the metabolism of APP through a nonamyloidgenic secretory pathway.

Original languageEnglish
Pages (from-to)9195-9198
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - 1 Oct 1993
Externally publishedYes


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