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 (A beta) peptide to neurological dysfunction in Alzheimer's disease (AD). Insoluble A beta 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 A beta, sugars, and Cu2+ in the oxidative stress mechanism of AD at the molecular level. Mass spectral (MS) analysis of the reactions of A beta 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 production by a cyt c assay showed that Lys-16 generated four times as much as Arg-5. Lys-16 and Arg-5 in A beta(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 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-A beta(1-40), sugars, and Cu2+-are necessary for DNA damage. It is concluded that the glycation of A beta(1-40) with sugars generates significant amounts of , owing to the rapid glycation of Lys-16 and Arg-5. In the presence of Cu2+, converts to hydroxyl radical (HO center dot), the source of oxidative stress in AD.