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. 2017 Dec;22(8):1211-1222. doi: 10.1007/s00775-017-1497-5. Epub 2017 Oct 16.

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 [Formula: see text] production by a cyt c assay showed that Lys-16 generated four times as much [Formula: see text] 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 [Formula: see text], owing to the rapid glycation of Lys-16 and Arg-5. In the presence of Cu2+, [Formula: see text] converts to hydroxyl radical (HO·), the source of oxidative stress in AD.

Keywords: Alzheimer’s disease; Amyloid beta; Copper; Glycation; Oxidative stress.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Arginine / metabolism*
  • Copper / pharmacology*
  • Cytochromes c / metabolism
  • DNA Damage
  • Deoxyguanine Nucleotides / metabolism
  • Glycosylation / drug effects
  • Guanosine Monophosphate / analogs & derivatives
  • Guanosine Monophosphate / metabolism
  • Lysine / metabolism*
  • Models, Molecular
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects*
  • Protein Conformation

Substances

  • 8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-monophosphate
  • Amyloid beta-Peptides
  • Deoxyguanine Nucleotides
  • Copper
  • 2'-deoxyguanosine 5'-phosphate
  • Guanosine Monophosphate
  • Cytochromes c
  • Arginine
  • Lysine