Phosphorylation of mitogen-activated protein kinase is altered in neuroectodermal cells overexpressing the human amyloid precursor protein 751 isoform

The aberrant expression or processing of the amyloid precursor protein (APP ) is the only known genetic basis for presenile familial Alzheimer's diseas e, and the molecular connection between APP and tau has been perplexing. At tention has focused on proline-directed serine/threonine kinases as mediati ng the cytoskeletal modifications of Alzheimer's disease, and we show that overexpression of APP can influence the activation of a candidate kinase, t he mitogen-activated protein kinase (MAPK). In murine embryonal carcinoma c ells stably transfected with the human 751 isoform of APP, we observed stea dy-state hyperactivation of p42(MAPK) concomitant with APP overexpression 3 days after neuroectodermal differentiation. In more mature differentiated cells, immunocytochemical analysis revealed enhanced basal somatic and nucl ear immunoreactivity for phosphorylated MAPK coupled with an attenuated pho sphorylation response to growth factor stimulation. Our results suggest tha t APP can influence the MAPK signaling pathway in such a way that the absol ute and time-dependent activation required for discrimination of the approp riate downstream response are compromised. Such an effect would have import ant consequences for the functioning of cells coincidentally expressing bot h proteins, a situation that occurs in neuronal populations vulnerable to A lzheimer's disease pathology. (C) 1999 Elsevier Science B.V. All rights res erved.