SECRETED BETA-AMYLOID PRECURSOR PROTEIN STIMULATES MITOGEN-ACTIVATED PROTEIN-KINASE AND ENHANCES TAU-PHOSPHORYLATION

Biological effects related to cell growth, as well as a role in the pa thogenesis of Alzheimer disease, have been ascribed to the beta-amyloi d precursor protein (beta-APP). Little is known, however, about the in tracellular cascades that mediate these effects. We report that the se creted form of beta-APP potently stimulates mitogen-activated protein kinases (MAPKs). Brief exposure of PC-12 pheochromocytoma cells to bet a-APP secreted by transfected Chinese hamster ovary cells stimulated t he 43-kDa form of MAPK by >10-fold. Induction of a dominant inhibitory form of ras in a PC12-derived cell line prevented the stimulation of MAPK by secreted beta-APP, demonstrating the dependence of the effect upon p21(ras). Because the microtubule-associated protein tau is hyper phosphorylated in Alzheimer disease, we sought and found a 2-fold enha ncement in tau phosphorylation associated with the beta-APP-induced MA PK stimulation. In the ras dominant inhibitory cell line, beta-APP fai led to enhance phosphorylation of tau. The data presented here provide a link between secreted beta-APP and the phosphorylation state of tau .