Several diseases share misfolding of different peptides and proteins as a key feature for their development. This is the case of important neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and type II diabetes mellitus. Even more, metal ions such as copper and zinc might play an important role upon interaction with amyloidogenic peptides and proteins, which could impact their aggregation and toxicity abilities. In this review, the different coordination modes proposed for copper and zinc with amyloid-β, α-synuclein and IAPP will be reviewed as well as their impact on the aggregation, and ROS production in the case of copper. In addition, a special focus will be given to the mutations that affect metal binding and lead to familial cases of the diseases. Different modifications of the peptides that have been observed and could be relevant for the coordination of metal ions are also described.

ROS production proceeds through a Cu–Aβ state in which Cu(i/ii) binds to the NH2 and COO– groups of Asp1 and a histidine.

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.

The use of a Cu(i) stabilizing ligand to target copper ions is a very promising approach against Alzheimer's disease.

Along with aggregation of the amyloid-β (Aβ) peptide and subsequent deposit of amyloid plaques, oxidative stress is an important feature in Alzheimer's disease. Cu bound to Aβ is able to produce reactive oxygen species (ROS) by the successive reductions of molecular dioxygen, and the ROS produced contribute to oxidative stress. In vitro, ascorbate consumption parallels ROS production, where ascorbate is the reductant that fuels the reactions. Because the affinity of Cu for Aβ is moderate compared to other biomolecules, the rate of ascorbate consumption is a combination of two contributions. The first one is due to peptide-unbound Cu and the second one to peptide-bound Cu complexes. In the present Article, we aim to determine the amounts of the second contribution in the global ascorbate consumption process. It is defined as the intrinsic rate of ascorbate oxidation, which mathematically corresponds to the rate at an infinite peptide to Cu ratio, i.e., without any contribution from peptide-unbound Cu. We show that, for the wild-type Cu(Aβ) complex, this value equals 10% of the value obtained for peptide-unbound Cu and that this value is strongly dependent on peptide alterations. By examination of the dependence of the intrinsic rate of ascorbate oxidation, followed by UV-vis spectroscopy, for several altered peptides, we determine some of the key residues that influence ROS production.

Tutorial focusing on the chemistry of mammalian metallothioneins, important to understand its biological functions in zinc and copper metabolism, detoxification and oxidative stress.

Alkyne gold(i) derivatives with the water soluble phosphanes PTA and DAPTA were described and their anticancer potential against the colon cancer cell line Caco-2 (PD7 and TC7 clones) was studied.

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