Neurotoxicity of advanced glycation end-products for cultured cortical neurons

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 process es. Incubation of cortical neurons with 5 immunochemically distinct AGEs, d esignated AGEs-1 to -5, produced a dose-dependent increase in neuronal cell -death, as assessed by MTT assay, Trypan blue and Hoechst 33258 staining. T he structural epitope designated AGE-2 was found to have the greatest cytop athic 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 ant ibodies. Distinct classes of AGE structures also have been established to c irculate in the blood of individuals with diabetes mellitus and end-stage r enal disease treated by hemodialysis (DM-HD). We fractionated serum from no rmal control and DM-HD patients by gel filtration and identified 2 fraction s that contained AGE epitopes-l to -5 and as well as the defined AGE struct ure 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 t hat the structural epitope AGE-2 is an important toxic moiety for neuronal cells.