Processing of Alzheimer β/A4 amyloid precursor protein: Modulation by agents that regulate protein phosphorylation

The turnover and processing of the Alzheimer β/A4 amyloid precursor protein (βAPP) 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 βAPP and increased the levels of 15- and 19-kDa peptides. These peptides appeared to be COOH-terminal fragments of βAPP, which arose when phorbol 12,13-dibutyrate increased the rate of proteolytic processing of mature forms of βAPP. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, also led to decreased levels of mature βAPP 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 βAPP. 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 β/A4 region of βAPP 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.