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

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 Cu 2+ 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 O 2 ∙ - production by a cyt c assay showed that Lys-16 generated four times as much O 2 ∙ - as Arg-5. Lys-16 and Arg-5 in Aβ 1–40 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 p K a 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—Aβ 1–40 , sugars, and Cu 2+ —are necessary for DNA damage. It is concluded that the glycation of Aβ 1–40 with sugars generates significant amounts of O 2 ∙ - , owing to the rapid glycation of Lys-16 and Arg-5. In the presence of Cu 2+ , O 2 ∙ - converts to hydroxyl radical (HO·), the source of oxidative stress in AD. Graphical Abstract