REGULATION OF SECRETION OF ALZHEIMER AMYLOID PRECURSOR PROTEIN BY THEMITOGEN-ACTIVATED PROTEIN-KINASE CASCADE

Activation of protein kinase C (PKC) regulates the processing of Alzhe imer amyloid precursor protein (APP) into its soluble form (sAPP) and amyloid beta-peptide (A beta), However, little is known about the inte rmediate steps between PKC activation and modulation of APP metabolism . Using a specific inhibitor of mitogen-activated protein (MAP) kinase kinase activation (PD 98059), as well as a dominant negative mutant o f MAP kinase kinase, we show in various cell lines that stimulation of PKC by phorbol ester rapidly induces sAPP secretion through a mechani sm involving activation of the MAP kinase cascade. In PC12-M1 cells, a ctivation of MAP ki nase by nerve growth factor was associated with st imulation of sAPP release. Conversely, M1 muscarinic receptor stimulat ion, which is known to act in part through a PKC-independent pathway, increased sAPP secretion mainly through a MAP kinase-independent pathw ay. A beta secretion and its regulation by PKC were not affected by PD 98059, supporting the concept of distinct secretory pathways for A be ta and sAPP formation.