SECRETED BETA-APP STIMULATES MAP KINASE AND PHOSPHORYLATION OF TAU INNEURONS

We have previously demonstrated that the secreted form of the beta-amy loid precursor protein (beta-APP) activates mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. beta-APP as well as oth er treatments that activate MAP kinase also enhance phosphorylation of the microtubule-associated protein tau in these cells. In this study, we extended this analysis to neurons. Using dissociated cultures of c ortical neurons, we found that exposure to beta-APP activated MAP kina se 4 and 7 days but not 1 day after plating. Phosphorylation of tau in neurons was measured by immunoreactivity with the AT8 antibody, which recognizes a phosphorylated epitope present in tau from paired helica l filaments. We found that activation of MAP kinase in neurons was ass ociated with increased amounts of AT8-reactive tau. These results supp ort a role for MAP kinase in transducing the biological effects of sec reted beta-APP on neurons and suggest possible mechanisms by which bet a-APP might be involved in the pathogenesis of Alzheimer's disease.