Roles of protein kinases in mediating adaptive neuronal responses to activation of signal transduction pathways are well known. Recent findings suggest that kinases may also be involved in pathological processes in the nervous system. The present study employed cultured human cerebral cortical neurons to test the hypothesis that overactivation of protein kinase C (PKC) can result in neurodegeneration. Phorbol 12-myristate 13-acetate (PMA), an activator of PKC, caused the degeneration of neurons over a period of 3-24 h. The PKC inhibitor H-7 prevented the neurodegeneration normally caused by PMA, and an inactive phorbol (4 alpha-phorbol 12,13-didecanoate; PDD) did not cause neurodegeneration. The neurodegeneration caused by PMA was independent of calcium influx. Immunoreactivity toward antibodies that recognize the microtubule-associated protein tau in Alzheimer neurofibrillary tangles (Alz-50 and 5E2) was greatly increased in neurons exposed to PMA. The antigenic changes were prevented by H-7. These findings indicate that high levels of activation of PKC can cause neurodegeneration and are consistent with the possibility that altered cellular signaling contributes to pathological neuronal degeneration in the intact nervous system.