Amyloid 3 protein (Af3) is a 40-43 amino acid peptide that Is associated with plaques in the brains of Alzheimer’s patients and is cytotoxic to cultured neurons. Using both primary central nervous system cultures and clonal cell lines, it is shown that a number of antioxidants protect cells from A3 toxicity, suggesting that at least one pathway to A3 cytotoxlcity results In free radical damage. A3 causes increased levels of H202and lipid peroxides to accumulate In cells. The Hz02degrading enzyme catalase protects cells from Aft toxicity. Clonal cell lines selected for their resistance to Af3 toxicity also become resistant to the cytolytic action of H201. In addltlon, Aft induces the activity of NF-KB, a transcrlption factor thought to be regulated by oxidative stress. Finally, Aft-induced H202 production and Af3 toxicity are blocked by reagents that Inhibit flavin oxidases, suggesting that Aft activates a member of this class of enzymes. These results show that the cytotoxic action of A3 on neurons results from free radical damage to susceptible cells.