Abstract
Extensive research has linked the amyloid-beta (Aβ) peptide to neurological dysfunction in Alzheimer’s disease (AD). Insoluble Aβ plaques in the AD patient brain contain high concentrations of advanced glycation end-products (AGEs) as well as transition metal ions. This research elucidated the roles of Aβ, sugars, and Cu2+ in the oxidative stress mechanism of AD at the molecular level. Mass spectral (MS) analysis of the reactions of Aβ with two representative sugars, ribose-5-phosphate (R5P) and methylglyoxal (MG), revealed Lys-16 and Arg-5 as the primary glycation sites. Quantitative analysis of superoxide \(\left({\text{O}}_2^{\bullet-}\right)\) production by a cyt c assay showed that Lys-16 generated four times as much \({\text{O}}_2^{\bullet-}\) as Arg-5. Lys-16 and Arg-5 in Aβ1–40 are both adjacent to histidine residues, which are suggested to catalyze glycation. Additionally, Lys-16 is close to the central hydrophobic core (Leu-17–Ala-21) and to His-13, both of which are known to lower the pKa of the residue, leading to increased deprotonation of the amine and an enhanced glycation reactivity compared to Arg-5. Gel electrophoresis results indicated that all three components of AD plaques—Aβ1–40, sugars, and Cu2+—are necessary for DNA damage. It is concluded that the glycation of Aβ1–40 with sugars generates significant amounts of \({\text{O}}_2^{\bullet-}\), owing to the rapid glycation of Lys-16 and Arg-5. In the presence of Cu2+, \({\text{O}}_2^{\bullet-}\) converts to hydroxyl radical (HO·), the source of oxidative stress in AD.
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Acknowledgements
The authors thank Middlebury College, and the Arnold and Marble Beckman Foundation for their financial support for this work. We also acknowledge Ms. Jody Smith and Dr. Royston Quintyn for their help with mass spectrometry and MS data analysis.
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Fica-Contreras, S.M., Shuster, S.O., Durfee, N.D. et al. Glycation of Lys-16 and Arg-5 in amyloid-β and the presence of Cu2+ play a major role in the oxidative stress mechanism of Alzheimer’s disease. J Biol Inorg Chem 22, 1211–1222 (2017). https://doi.org/10.1007/s00775-017-1497-5
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DOI: https://doi.org/10.1007/s00775-017-1497-5