Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.

The imidazole ring is part of the lateral chain of histidine. One of the main features of this amino acid is the ability to coordinate copper, especially Cu²⁺, because of the intermediate base nature of its imidazole ring, which has a great biological relevance. Proteins such as cytochrome c oxidase, a crucial enzyme in the respiratory chain, and β-amyloid peptide, implicated in the pathology of Alzheimer's disease, are examples of proteins containing histidines in their coordination sphere. Several studies indicate that the presence of this metal ion produces a decrease in the pK_a of the imidazole ring of histidine. However, there are no reports of systematic studies of pK_a variation in these types of metal cation complexes. In this work we use density functional theory to study the dependence of imidazole pK_a with the number of imidazole rings in Cu²⁺ coordination environments. The pK_a of isolated imidazole (ImH), and the pK_a of imidazole in Cu²⁺(ImH)_m(H₂O)_4−m (m = 1–3) complexes have been studied using two different functionals, B3LYP and MPWB1K, which have different percentage of exact exchange, and the highly-correlated CCSD(T) method. Results show that imidazole pK_a decreases between 2 and 7 units depending on the method employed and the number of imidazole rings coordinating the metal cation. Taking into account that the pK_a of imidazole is 14, this decrease could be relevant in biological processes.

We investigate, by means of density-functional theory, the binding of dioxygen to Cu(I)–amyloid β (Aβ), one of the first steps in the oxidation of ascorbate by dioxygen. Cu, Aβ, ascorbate and dioxygen are all present in the synapse during neurodegeneration, when the above species can trigger an irreversible oxidative stress inducing the eventual death of neurons. The binding of dioxygen to Cu(I) is possible and its role in dioxygen activation of Cu ligands and of residues in the first coordination sphere is described in atomic detail. Dioxygen is activated when a micro-environment suitable for a square-planar Cu²⁺ coordination is present and a negatively charged group like Asp 1 carboxylate takes part in the Cu coordination anti to O₂.