Current understanding of metal-dependent amyloid-β aggregation and toxicity

Abstract

The discovery of effective therapeutics targeting amyloid-β (Aβ) aggregates for Alzheimer's disease (AD) has been very challenging, which suggests its complicated etiology associated with multiple pathogenic elements. In AD-affected brains, highly concentrated metals, such as copper and zinc, are found in senile plaques mainly composed of Aβ aggregates. These metal ions are coordinated to Aβ and affect its aggregation and toxicity profiles. In this review, we illustrate the current view on molecular insights into the assembly of Aβ peptides in the absence and presence of metal ions as well as the effect of metal ions on their toxicity.

Fig. 1. Structures of Aβ peptides and their aggregation. (a) Amino acid sequences of Aβ₄₀ and Aβ₄₂. (b) Examples of previously reported Aβ monomers (for Aβ₄₀, PDB 2LFM; for Aβ₄₂, PDB 1IYT). (c) Example of a previously reported Aβ₄₂ fibril (PDB 1IYT). The salt bridges that contribute to the stabilization of fibrillar forms are indicated in I–IV. (d) Schematic view of a fibrillar structure of Aβ₄₂ with amino acid residues colored according to their polarity and charge states. Three His residues in Aβ are classified into polar amino acid residues based on its chemical environment at pH 7.4. (e) Schematic representation of relative concentrations of oligomeric and fibrillary Aβ as a function of time. The increase in the concentration of fibrils in a sigmoidal manner presents the macroscopic aggregation of Aβ that is typically divided into lag, elongation, and plateau phases. Reproduced with permission from ref. . Copyright© 2020 Springer Nature. (f) Schematic illustration of microscopic steps involved in Aβ aggregation. Reproduced with permission from ref. . Copyright© 2022 AIP Publishing.

Fig. 2. Metal-binding properties of Aβ. Examples of structures of (a) Cu(ii)–Aβ, (b) Cu(i)–Aβ, (c) their in-between state, and (d) Zn(ii)–Aβ. Possible fifth ligands on the metal centers are omitted in the figure for clarity. (e) Scheme of ROS formation catalyzed by Cu(i/ii) in the presence of a reductant and redox potentials of the species involved in the reactions with respect to the normal hydrogen electrode (NHE). Cellular reductants include ascorbate and glutathione.

Fig. 3. Influence of metal ions on the alignment and conformation of model peptides. (a) Possible metal-binding modes of Aβ_11–28 depending on the type of metal ions and the metal-to-peptide stoichiometry. The sub-equimolar concentration of Zn(ii) can bridge two Aβ_11–28 peptides, stabilizing their interaction and preferably forming β-sheets. In the presence of an equimolar amount of Cu(ii), Aβ_11–28 can wrap around the metal ion and, consequently, reduce the number of hydrogen bonds, which possibly hinders the alignment required to form β-sheets. Reproduced with permission from ref. . Copyright© 2010 Springer Nature. (b) Conformational change of the coiled coil peptide (i.e., i,i+7) upon the addition of metal ions. A helical wheel diagram presents the amino acid residues of the coiled coil peptide in a heptad repeat labeled as (a–g). The His residues that participate in metal binding are highlighted in red. Abz introduced at the N-terminal of the peptide indicates o-aminobenzoic acid. Cu(ii) contributes to the conversion of the coiled coil peptide into the β-sheet-rich peptide, while Zn(ii) stabilizes the α-helical structure of the peptide.

Fig. 4. Possible toxic events induced by Aβ oligomers and fibrils with and without metal ions in cellular environments. In the absence of metal ions, Aβ species can interact with cellular membranes, changing their secondary structures at the surface or within the cell membranes. Consequently, Aβ can aggregate near the membrane and form a membrane-permeable pore structure that possibly controls the influx and efflux of neurotransmitters [e.g., Ca(ii)]. Such processes can be altered upon interaction of Cu(ii) and Zn(ii) with Aβ species near the membranes. Extracellular Aβ aggregates can be internalized by endocytosis and the receptors in cellular membranes. The intracellular accumulation of Aβ aggregates can disrupt subcellular events.