JBIC Journal of Biological Inorganic Chemistry

, Volume 24, Issue 8, pp 1217–1229 | Cite as

Copper, dityrosine cross-links and amyloid-β aggregation

  • Guillem Vázquez
  • Ana B. CaballeroEmail author
  • Jakub Kokinda
  • Ana Hijano
  • Raimon SabatéEmail author
  • Patrick GamezEmail author
Original Paper
Part of the following topical collections:
  1. Metal Ions and Degenerative Diseases


Copper is involved in Alzheimer’s disease (AD) where it appears to affect the aggregation of amyloid-β (Aβ) and to catalyze the production of reactive oxygen species (ROS). Oxidative stress apparently produces Aβ dimers that are covalently linked through two tyrosine residues. Such dityrosine cross-links are considered as potential markers of the disease and seem to be implicated in the pathological disorder. In the present study, pure o,o′-dityrosine (diY) was prepared enzymatically (with horseradish peroxidase; HRP), which was subsequently used to construct calibration lines aimed at quantifying nanomolar amounts of diY in reaction mixtures by fluorescence spectroscopy. Hence, diY concentrations down to 67 nM could be determined, which allowed to find that ca. 3% of dityrosine-bridged dimers of Aβ(1–40) were produced after 3 days at 37 °C in the presence of copper and dihydrogen peroxide. These cross-linked dimers in the presence of copper(II) ions completely inhibit the typical aggregation of Aβ, since β sheets could not be detected applying the usual Thioflavin T (ThT) method. Furthermore, the use of a potent Cu(II) chelator, such as the ATCUN tripeptide, l-histidyl-l-alanyl-l-histidine (HAH), efficiently prevented the copper-mediated generation of ROS and the associated dityrosine-bridged Aβ dimers, suggesting that such metal chelators may find future applications in the field of anti-AD drug design.


Alzheimer’s disease Oxidative stress Protein cross-linking Radicals Inhibitor 



The authors gratefully acknowledge financial support from MICINN (project CTQ2017-88446-R AEI/FEDER, UE). ABC thanks the European Union’s Horizon 2020 research and innovation programme for her Marie Skolodowska-Curie Grant No. 656820. PG acknowledges the Institució Catalana de Recerca i Estudis Avançats (ICREA).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

775_2019_1734_MOESM1_ESM.pdf (469 kb)
Supplementary material 1 (PDF 469 kb)


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Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  1. 1.Inorganic Chemistry Section, Department of Inorganic and Organic ChemistryUniversity of BarcelonaBarcelonaSpain
  2. 2.Institute of Nanoscience and Nanotechnology (IN2UB)Universitat de BarcelonaBarcelonaSpain
  3. 3.Departament de Fisicoquímica, Facultat de Farmàcia i Ciències de l’AlimentacióUniversitat de BarcelonaBarcelonaSpain
  4. 4.Catalan Institution for Research and Advanced Studies (ICREA)BarcelonaSpain

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