REGULATION OF AMYLOID PRECURSOR PROTEIN CATABOLISM INVOLVES THE MITOGEN-ACTIVATED PROTEIN-KINASE SIGNAL-TRANSDUCTION PATHWAY

Catabolic processing of the amyloid precursor protein (APP) is subject to regulatory control by protein kinases. We hypothesized that this r egulation involves sequential activation of the enzymes mitogen-activa ted protein kinase kinase (MEK) and extracellular signal-regulated pro tein kinase (ERK). In the present investigation, we provide evidence t hat MEK is critically involved in regulating APP processing by both ne rve growth factor and phorbol esters. Western blot analysis of the sol uble N-terminal APP derivative APP(s) demonstrated that the synthetic MEK inhibitor PD 98059 antagonized nerve growth factor stimulation of both APP(s) production and ERK activation in PC12 cells. Moreover, PD 98059 inhibited phorbol ester stimulation of APP(s) production and act ivation of ERK in both human embryonic kidney cells and cortical neuro ns. Furthermore, overexpression of a kinase-inactive MEK mutant inhibi ted phorbol ester stimulation of APP secretion and activation of ERK i n human embryonic kidney cell lines. Most important, PD 98059 antagoni zed phorbol ester-mediated inhibition of A beta secretion from cells o verexpressing human APP(695) carrying the ''Swedish mutation.'' Taken together, these data indicate that MEK and ERK may be critically invol ved in protein kinase C and nerve growth factor regulation of APP proc essing. The mitogen-activated protein kinase cascade may provide a nov el target for altering catabolic processing of APP.