Phosphorylation of alzheimer amyloid precursor protein by protein kinase C

Abstract

The βA4 amyloid precursor protein is a membrane protein with one transmembrane domain. 14–16,22,27,28,32,33 The accumulation and deposition of β/A4 amyloid protein in Alzheimer's disease is thought to be brought about by altered processing of β/A4 amyloid precursor protein. 7,9,35,36 Activation of protein kinase C and/or inhibition of protein phosphatases 1 and 2A results in an increase in the proteolytic processing 3 and secretion 4 of β/A4 amyloid precursor protein. These effects might result either from phosphorylation of β/A4 amyloid precursor protein by protein kinase C or from phosphorylation of components of the β/A4 amyloid precursor protein processing apparatus. 3,4,9 We have previously reported phosphorylation by protein kinase C of a synthetic peptide corresponding to part of the cytoplasmic domain of β/A4 amyloid precursor protein. 10 However, it was not known whether β/A4 amyloid precursor protein holoprotein was phosphorylated in its native conformation in the cell membrane. Using a PC12 (rat pheochromocytoma) semi-intact cell system, we now report that mature isoforms of β/A4 amyloid precursor protein are phosphorylated by protein kinase C at Ser 655. Five COOH-terminal fragments which are generated by processing of mature β/A4 amyloid precursor protein were also phosphorylated by protein kinase C at Ser 655. The results support the idea that the β/A4 amyloid precursor protein haloprotein is a physiological substrate for protein kinase C. These observations should facilitate our understanding of the relationship between altered protein phosphorylation and β/A4 amyloid production.