Effects of methylglyoxal on amyloid‐beta peptide

Abstract

Diabetics exhibit elevated levels of carbohydrates and their oxidized byproducts such as methylglyoxal (MGO). With the excess production and accumulation of the amyloid‐beta peptide (ABP) in AD, the linkage between diabetes and AD may involve ABP and MGO. We studied the effects of MGO‐induced ABP modification on conformational properties. Human isoform ABP fragment 1–42 was used in our study. Fluorescence and absorbance spectroscopy assessed MGO‐induced production of advanced glycation endproducts (AGEs), size exclusion chromatography monitored conformational changes, and thioflavin T fluorescence tracked fibrillation. MGO decreased the amount of high molecular weight (HMW) ABP aggregate and increased the low molecular weight (LMW) species relative to the control. Products obtained from incubation of MGO with free arginine, which absorbed in the 220nm range, also appear in HMW ABP when incubated with MGO. The LMW ABP species contained an MGO‐derived adduct that absorbed in the 280nm range, suggesting that conformational differences in the structures may promote reactivity to different amino acid residues. MGO affected the rates of ABP aggregation as compared with control, indicating that AGEs may influence ABP packing densities. These observations suggest a plausible molecular explanation for the relationship between diabetes and AD, providing novel avenues for therapeutic intervention.