Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid-β Stability, Oligomerization, and Aggregation

Abstract

3؉ also inhibits fibril formation; however, the annular oligomers co-exist in the aggregation pathway. In conclusion, Zn 2؉ , Cu 2؉ , Fe 3؉ , and Al 3؉ adopt distinct folding and aggregation mechanisms to affect A␤, where A␤ destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular A␤ oligomer formation upon metal ion binding. The brain deposition of amyloid plaques composed of A␤2 is the pathological hallmark of AD (1, 2). A␤ is generated from sequential cleavages of amyloid precursor protein by ␤-and ␥-secretases (3, 4). The predominant A␤ isoforms are A␤40 and A␤42, which differ in two residues at the C terminus, where A␤42 is less abundant but more neurotoxic (5-8). A␤ is a natively unfolded protein prone to aggregating into cross-␤-amyloid fibrils through a nucleation-dependent polymerization pathway (9). A␤ aggregation is considered the major culprit in AD, in which the A␤ oligomers, but not fibrils, better correlate with cognitive impairment and synaptic dysfunction (10). A␤ oligomers are referred to various different metastable intermediates found in the aggregation, including low molecular weight oligomers, spherical oligomers, A␤-derived diffusible ligands, globulomers, annular protofibrils, A␤56*, and curvilinear protofibrils (11)(12)(13)(14)(15)(16)(17)(18) (24 -25). These facts indicate that the elevation of the metal ions is relevant to AD pathology.A␤ is able to bind to the metal ions (22, 23). A␤ ion coordination, binding affinity, and induced aggregation have been studied intensively in various conditions; however, the results and mechanisms remain inconclusive. A␤-Cu 2ϩ coordination involves three intramolecular histidines (i.e. His-6, His-13, and His-14) in A␤ (26 -28), with the fourth coordinate being either the amino group of the N terminus (29), an oxygen from Tyr-10 (30), or an oxygen from Glu-3 (29). The A␤-Zn 2ϩ complex is reportedly more complicated. A similar coordination with Cu 2ϩ has been proposed for Zn 2ϩ using the three histidines and the N terminus (31, 32). Both intermolecular A␤-Cu 2ϩ and A␤-Zn 2ϩ coordination have been reported via histidine bridges (28, 30 -33). Fe 3ϩ has also been shown to interact with histidines (37). Dissociation constants for the binding affinity of

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

“…This indicates that the remaining soluble peptide was already fully loaded with Cu(II), and that the aggregation of a soluble A␤-Cu y complex is rate-limiting as observed under equimolar conditions. Recently it has been shown that Cu(II) decreases the hydrophobic exposed protein surfaces of A␤ when added in supraequimolar ratios (43), which may explain the observed increased solubility of the A␤-Cu complex.…”

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

“…The experimental conditions for Ab 1-42 fibrillization have been described in previous reports. 7 The increase in the intensity of the fluorescence signal of ThT associated with Ab 1-42 fibrillization is depicted in Figure 8(A). The time course for the formation of the fibrils was also observed through continuous monitoring of the changes in the ThT fluorescence intensity at 480 nm over the course of 24 h; this time period is sufficient to allow fibril formation under incubation and stirring conditions.…”

“…Some reports have demonstrated that the presence of Cu 21 favors fibril formation, 10 while other recent studies suggested that Cu 21 might inhibit Ab 1242 fibril formation. 7 In addition, numerous compounds have been found to reduce Ab 1242 aggregation in vitro. 11,12 However, the usefulness of these compounds as inhibitors of Ab 1242 aggregation remains speculative due to their lack of specificity and/or unknown mechanism of action.…”

“…One of the metals that has attracted attention is copper (Cu 21 ), whose concentration is threefold greater in AD patients than in normal patients, with concentrations between 340 and 400 mM. 6,7 The interaction between Ab-fibrils and Cu 21 is important not only because of its role in amyloidosis but also because it has been associated with the generation of oxidative stress. 8 Therefore, several experimental and computational methods have focused on the analysis of the interaction between Ab 1242 and Cu 21 .…”

The Ins and Outs of Nanoparticle Technology in Neurodegenerative Diseases and Cancer

“…D-penicillamine, a copper chelating molecule, was shown to have an interest for ADtargeted therapy [187,188] since metal ions such as iron or copper are involved in the formation AD pathogenesis due to the binding of APP, their accumulation in the AD brain [177,189,190]. This compound, already used in therapy of other pathologies such as the Wilson's disease affecting the liver, rheumatoidis and lead poisoning was tested as a nanoformulation where it was covalently linked to NPs in vitro and was successfully shown to disaggregate Aβ peptide [191].…”