Amyloid beta protein (A beta) is a 40 to 43 amino acid peptide which is associated with plaques in the brains of Alzheimer's patients and is cytotoxic to cultured neurons. A number of antioxidants protect both primary central nervous system (CNS) cultures and clonal cell lines from A beta toxicity, suggesting that one pathway to A beta cytotoxicity results in free radical damage. A beta causes increased levels of H2O2 and lipid peroxides to accumulate in cells. The H2O2 degrading enzyme catalase protects cells from A beta toxicity. Clonal cell lines selected for their resistance to A beta toxicity also become resistant to the cytolytic action of H2O2. In addition, A beta induces NF-kB activity, a transcription factor thought to be regulated by oxidative stress. Finally, A beta induced H2O2 production and A beta toxicity are blocked by reagents which inhibit flavin oxidases, suggesting that A beta activates a member of this class of enzymes. These results show that the cytotoxic action of A beta on neurons results from free radical damage to susceptible cells (Behl et al., 1994b).