How senile plaques and neurofibrillary tangles are linked represents a major gap in our understanding of the pathophysiology of Alzheimer's disease (AD). We have previously shown that the addition of fibrillar beta-amyloid (Abeta) to mature hippocampal neurons results in progressive neuritic degeneration accompanied by the enhanced phosphorylation of adult tau isoforms. In the present study, we sought to obtain more direct evidence of the signal transduction pathway(s) activated by fibrillar Abeta leading to tau phosphorylation and the generation of dystrophic neurites. Our results indicated that fibrillar Abeta induced the progressive and sustained activation of the mitogen-activated protein kinase (MAPK) in mature hippocampal neurons. On the other hand, the specific inhibition of the MAPK signal transduction pathway by means of PD98059, a MAPK kinase (MEK) specific inhibitor, prevented the phosphorylation of tau (at Ser199/Ser202) induced by fibrillar Abeta. In addition, the inhibition of MAPK activation partially prevented neurite degeneration. Taken collectively, our results suggest that the sustained activation of the MAPK signal transduction pathway induced by fibrillar Abeta may lead to the abnormal phosphorylation of tau and the neuritic degeneration observed in AD.