Metabolism of Alzheimer β-amyloid precursor protein: Regulation by protein kinase A in intact cells and in a cell-free system

Various compounds that affect signal transduction regulate the relative utilization of alternative processing pathways for the β-amyloid precursor protein (βAPP) in intact cells, increasing the production of nonamyloidogenic soluble βAPP (sβAPP) and decreasing that of amyloidogenic β-amyloid peptide. In a recent study directed toward elucidating the mechanisms underlying phorbol ester-stimulated sβAPP secretion from cells, it was demonstrated that protein kinase C increases the formation from the trans-Golgi network (TGN) of βAPP-containing secretory vesicles. Here we present evidence that forskolin increases sβAPP production from intact PC12 cells, and protein kinase A stimulates formation from the TGN of βAPP- containing vesicles. Although protein kinase A and protein kinase C converge at the level of formation from the TGN of βAPP-containing vesicles, additional evidence indicates that the regulatory mechanisms involved are distinct.