Recent evidence suggests that amyloid beta protein (A beta) mediates the neurotoxicity observed in Alzheimer's disease (AD). Little is known, however, about the cytotoxic pathway leading to nerve cell death. Using a rat brain cell line which is sensitive to A beta, it is shown that a 50-60 kDa protein becomes more phosphorylated when cells are exposed to A beta. Several kinase and phosphatase inhibitors block both the increase in phosphorylation of the 50-60 kDa protein and A beta toxicity. In contrast, a tyrosine kinase inhibitor blocks toxicity at a step which is distinct from the phosphorylation of this protein. A beta also causes a general increase in overall phosphatase activity. It is therefore likely that a protein phosphorylation cascade is involved in A beta toxicity.