Protein phosphorylation inhibits production of Alzheimer amyloid β/A4 peptide

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.