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. 1990 Aug;87(15):6003–6006. doi: 10.1073/pnas.87.15.6003

Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation.

J D Buxbaum 1, S E Gandy 1, P Cicchetti 1, M E Ehrlich 1, A J Czernik 1, R P Fracasso 1, T V Ramabhadran 1, A J Unterbeck 1, P Greengard 1
PMCID: PMC54458  PMID: 2116015

Abstract

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.

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Selected References

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