Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer's Disease: Experimental and Computational Insights

Abstract

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.

Figure 1

Degradation pathways for the APP. The amyloidogenic route produces the Aβ peptide.

Figure 2

Proposed mechanism for the oxidative stress mediated by metal cations and Aβ peptide.

Figure 3

Coordination spheres for Cu-Aβ complexes at low (6.4) and high (>7.4) pH.

Scheme 1. Computational Protocol for the Construction of Metal-Peptide Complexes

Adapted with permission from ref (104). Copyright 2015 AIP Publishing.

Figure 4

Fe-Aβ model systems and calculated SRP values. Adapted from ref (123). Copyright 2022 Royal Society of Chemistry.

Scheme 2. Computational Methodology for the Construction and Evaluation of Al-Aβ Models

Adapted with permission from ref (137). Copyright 2017 Royal Society of Chemistry.

Scheme 3. Example of a Computational Protocol with the Essential Steps for the Design and Evaluation of Multifunctional Chelators

Figure 5

Computational protocol for the selection of third-generation chelating agents. Adapted with permission from ref (172). Copyright 2021 IOS Press.