The Maillard reaction that leads to the formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients and in aging. AGEs are believed also to contribute to the pathology of Alzheimer disease (AD) and other neurodegenerative processes. Incubation of cortical neurons with 5 immunochemically distinct AGEs, designated AGEs-1 to -5, produced a dose-dependent increase in neuronal cell-death, as assessed by MTT assay, Trypan blue and Hoechst 33258 staining. The structural epitope designated AGE-2 was found to have the greatest cytopathic effect and the neurotoxicity of AGE-2 was neutralized by the addition of an anti-AGE-2-specific antibody, but not by other types of anti-AGE antibodies. Distinct classes of AGE structures also have been established to circulate in the blood of individuals with diabetes mellitus and end-stage renal disease treated by hemodialysis (DM-HD). We fractionated serum from normal control and DM-HD patients by gel filtration and identified 2 fractions that contained AGE epitopes-1 to -5 and as well as the defined AGE structure carboxymethyllysine (CML). The addition of these 2 fractions led to the death of cultured neuronal cells and this cytotoxic effect was completely prevented by the addition of the anti-AGE-2-specific antibody. We propose that the structural epitope AGE-2 is an important toxic moiety for neuronal cells.