Mutual interference of Cu and Zn ions in Alzheimer's disease: perspectives at the molecular level

Abstract

While metal ions such as copper and zinc are essential in biology, they are also linked to several amyloid-related diseases, including Alzheimer's disease (AD). Zinc and copper can indeed modify the aggregation pathways of the amyloid-β (Aβ) peptide, the key component encountered in AD. In addition, the redox active copper ions do produce Reactive Oxygen Species (ROS) when bound to the Aβ peptide. While Cu(i) or Cu(ii) or Zn(ii) coordination to the Aβ has been extensively studied in the last ten years, characterization of hetero-bimetallic Aβ complexes is still scarce. This is also true for the metal induced Aβ aggregation and ROS production, for which studies on the mutual influence of the copper and zinc ions are currently appearing. Last but not least, zinc can strongly interfere in therapeutic approaches relying on copper detoxification. This will be exemplified with a biological lead, namely metallothioneins, and with synthetic ligands.

Fig. 1. Proposed coordination modes of Cu(ii), Cu(i), Zn(ii) and the mixed metal Cu(ii),Zn(ii) or Cu(i),Zn(ii) complexes^, based on experimental results and bibliographic data. Affinity constant values (K_a) at pH 7.4 for Cu(ii), Cu(i)^, and Zn(ii) are given in M^–1 (bold, purple).

Fig. 2. This figure resumes the aggregation with different Cu(ii) : Zn(ii) : Aβ ratios. Zn is the ion that dominates the Aβ metal-induced assembly even in the presence of Cu. For all of these aggregation experiments, metal ions have been added at the beginning, i.e. these are metal-induced aggregations.

Fig. 3. ROS production from Cu–Aβ complexes and the classical assays for the detection of ROS produced (O₂˙^–, H₂O₂, HO˙,) and indirect monitoring of Asc consumption.

Fig. 4. Panel A. This part represents the identical ROS production of a monomeric monometallic Cu–Aβ complex and of a monomeric hetero-bimetallic Cu,Zn–Aβ complex. Panel B. This part represents the ROS production by different Cu(ii) : Aβ ratios and by different states of aggregation of the peptide: fibrils produce less ROS than monomers, for the 0.5 : 1 ratio.^, Panel C. This last part compares the ROS production by amorphous aggregates of Cu(ii)–Aβ to the ROS production of aggregates in the presence of Zn(ii). Note that for all of the aggregation experiments, metal ions have been added at the beginning, i.e. these are metal-induced aggregations.

Fig. 5. Left panel. Representation of the importance of the affinity constant (written A) of the chelator in order to remove Cu from the Aβ peptide. Higher the affinity constant of the ligand is, higher is its efficiency in the removal of the metal ion from the peptide. Right panel. Representation of the importance of the selectivity (written S) of the ligand compared to the peptide one. Higher the selectivity of the ligand is compared to the peptide one, higher is its efficiency in the removal of Cu(ii) ion from the peptide in the presence of Zn(ii).

Fig. 6. Representation of the swap of metallic ions (Cu(ii) in red and Zn(ii) in green) between Aβ peptide and Zn₇-MT-3 (left) or a synthetic chelator, preloaded with Zn(ii) (right). The impact on the ROS production is also illustrated.

Elena Atrián-Blasco (right), Amandine Conte-Daban (left) and Christelle Hureau (middle)