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.

N4‐Tetradentate Chelators Efficiently Regulate Copper Homeostasis and Prevent ROS Production Induced by Copper‐Amyloid‐β1–16

“…The mean copper concentration in human frontal lobe and cerebellum has been reported to be in the range of 60-110 μM 4. The zinc/copper ratio can be as high as 10 to 100, in glutamatergic neurons 5a. Therefore, any attempt to regulate copper homeostasis and to inhibit copper-induced oxidative stress in the brain, must take into account this zinc-rich environment.5b…”

“…In this view, some of us reported the capacity of a water-soluble negatively charged chelator named L2 (Figure 1) to remove copper from copper-loaded Aβ in the presence of zinc in order to illustrate the importance of the Cu selectivity on ROS formation 5. This N 2 O 2 chelator, based on a Schiff-base scaffold, was able to inhibit the reductive activation of dioxygen in the presence of 1 molar equivalent (mol equiv) of Zn(II) but failed to stop ROS production in the presence of 5 mol equiv of Zn(II) during the ascorbate consumption 5a. In addition, as pointed out in the article, the ligand L2 is not able to cross the BBB (logP = – 3.7).…”

“…Since both TMDQ20 and compound 1 efficiently inhibited the ascorbate oxidation induced by Cu-Aβ 1-16 in the presence of 3 mol equiv of Zn 2+ , we decided to investigate the same reaction with a very large excess of zinc, 100 mol equiv of zinc with respect to copper, a Zn/Cu ratio that has been proposed to be biologically relevant 5. In these conditions, Cu-Aβ 1-16 induced 48% of ascorbate oxidation in 5 min, and 86% in 10 min (Figure 5, trace a).…”

“…These tetradendate ligands TDMQ20 and 1 , that specifically chelate Cu(II) in a N 4 -square planar fashion, are able to immediately and completely stop the in vitro ongoing aerobic oxidation of ascorbate induced by Cu-Aβ 1-16 , even in the presence of 100 mol equiv of Zn(II) with respect to copper ions, while the N 2 O 2 -tetradentate ligand L2, able to chelate copper with metal/ligand stoichiometry = 1/1, was efficient only in the presence of a stoichiometric amount of zinc 5. PBT2, whose copper complex has a N 3 O 2 coordination sphere, and a metal/ligand stoichiometry = 1/2,16 failed to inhibit oxygen reduction either in the presence or in the absence of zinc.…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…As recently studied for A [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] , [137] the interference of Zn in Cu II binding should be addressed in particular. Aggregation studies of N-terminally truncated A peptides in the presence of Cu II are too scarce as well.…”