Mercury and Alzheimer’s Disease: Hg(II) Ions Display Specific Binding to the Amyloid-β Peptide and Hinder Its Fibrillization

Wallin, Cecilia; Friedemann, Merlin; Sholts, Sabrina B.; Noormägi, Andra; Svantesson, Teodor; Jarvet, Jüri; Roos, Per M.; Palumaa, Peep; Gräslund, Astrid; Wärmländer, Sebastian K.T.S.

doi:10.3390/biom10010044

Cited by 29 publications

(90 citation statements)

References 169 publications

(178 reference statements)

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“…But also other metal ions may take key roles, e.g. through exogenous contamination and competition with the same binding ligands as endogenous metal ions (13,(19)(20)(21)(22)(23). Here we use metal ions in substoichiometric concentrations as amyloid aggregation modulators to disturb the aggregating system to obtain further insights into the fundamental self-assembly mechanisms.…”

Section: ________________________________________mentioning

confidence: 99%

Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation–inert complex

Wallin

Jarvet

Biverstål

et al. 2020

Journal of Biological Chemistry

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A detailed understanding of the molecular pathways for amyloid-β (Aβ) peptide aggregation from monomers into amyloid fibrils, a hallmark of Alzheimer's disease, is crucial for the development of diagnostic and therapeutic strategies. We investigate the molecular details of peptide fibrillization in vitro by perturbing this process through addition of differently charged metal ions. Here, we used a monovalent probe, the silver ion, that, similarly to divalent metal ions, binds to monomeric Aβ peptide and efficiently modulates Aβ fibrillization. On the basis of our findings, combined with our previous results on divalent zinc ions, we propose a model that links the microscopic metal-ion binding to Aβ monomers to its macroscopic impact on the peptide self-assembly observed in bulk experiments. We found that substoichiometric concentrations of the investigated metal ions bind specifically to the N-terminal region of Aβ, forming a dynamic, partially compact complex. The metal-ion bound state appears to be incapable of aggregation, effectively reducing the available monomeric Aβ pool for incorporation into fibrils. This is especially reflected in a decreased fibril-end elongation rate. However, because the bound state is significantly less stable than the amyloid state, Aβ peptides are only transiently redirected from fibril formation, and eventually almost all Aβ monomers are integrated into fibrils. Taken together, these findings unravel the mechanistic consequences of delaying Aβ aggregation via weak metal-ion binding, quantitatively linking the contributions of specific interactions of metal ions with monomeric Aβ to their effects on bulk aggregation.

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confidence: 99%

Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation–inert complex

Wallin

Jarvet

Biverstål

et al. 2020

Journal of Biological Chemistry

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“…However, not all metal ions interfere with tyrosine fluorescence, and initial experiments showed that addition of Li + ions does not affect the Aβ 40 fluorescence. The binding affinity of Li + ions to Aβ 40 was therefore evaluated from binding competition experiments with Cu 2+ ions (Danielsson et al ., 2007; Wallin et al ., 2020), which induce much stronger tyrosine fluorescence quenching when bound to the peptide than when free in the solution (Lindgren et al ., 2013). Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The binding affinity between Aβ 40 peptides and Li + ions was evaluated from Cu 2+ / Li + binding competition experiments (Wallin et al ., 2020). The affinity of the Cu 2+ ·Aβ 40 complex was measured via the quenching effect of Cu 2+ ions on the intrinsic fluorescence of Y10, which is the only fluorophore in native Aβ peptides.…”

Section: Methodsmentioning

confidence: 99%

“…They have limited solubility in water due to the hydrophobicity of the central and C-terminal Aβ segments, which may fold into a hairpin conformation upon aggregation (Abelein et al ., 2014; Baronio et al ., 2019). The charged N-terminal segment is hydrophilic and readily interacts with cationic molecules and metal ions (Luo et al ., 2013; Luo et al ., 2014; Tiiman et al ., 2016; Wallin et al ., 2016; Wallin et al ., 2017; Owen et al ., 2019; Wallin et al ., 2020), while the hydrophobic C-terminal segment can interact with membranes where Aβ may exert its toxicity (Österlund et al ., 2018; Wärmländer et al ., 2019). The interactions between Aβ and metal ions are of particular interest (Duce et al ., 2011; Wärmländer et al ., 2013; Mital et al ., 2015; Wärmländer et al ., 2019; Wallin et al ., 2020), as altered metal concentrations indicative of metal dyshomeostasis are a prominent feature in the brains and fluids of AD patients (Wang et al ., 2015; Szabo et al ., 2016), and because AD plaques contain elevated amounts of metal ions of e.g.…”

Section: Introductionmentioning

confidence: 99%

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Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation

Berntsson

Paul

Vosough

et al. 2021

Preprint

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Alzheimer’s disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has showed promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with Aβ peptides and modulate their aggregation and toxicity. The interactions between Aβ peptides and Li+ ions have however not been well investigated. Here, we use a range of biophysical techniques to characterize in vitro interactions between Aβ peptides and Li+ ions. We show that Li+ ions display weak and non-specific interactions with Aβ peptides, and have minor effects on Aβ aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between Aβ peptides and Li+ ions.

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“…Aβ plaques contribute to neuronal loss and ultimate failure of cognitive function [ 7 ]. The interaction of Aβ peptides with ions of copper, zinc, iron, aluminium, manganese, or mercury may contribute to neuronal damage [ 8 , 9 , 10 ]. Once Aβ begins to accumulate, it then promotes the build-up of Tau [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

2020

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Aluminium (Al) is clearly neurotoxic and considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer’s disease (AD). Nevertheless, the link between AD pathology and Al is still open to debate. Therefore, we investigated here the interaction of aluminium ions with two Aβ peptide fragments and their analogues. First, we synthesised by the Fmoc/tBu solid-phase peptide synthesis (SPPS) strategy using an automated peptide synthesiser two new peptides starting from the Aβ(1–16) native peptide fragment. For this purpose, the three histidine residues (H6, H13, and H14) of the Aβ(1–16) peptide were replaced by three alanine and three serine residues to form the modified peptides Aβ(1–16)A36,13,14 and Aβ(1–16)S36,13,14 (primary structures: H-1DAEFRADSGYEVAAQK16-NH2 and H-1DAEFRSDSGYEVSSQK16-NH2). In addition, the Aβ(9–16) peptide fragment (H-9GYEVHHQK16-NH2) and its glycine analogues, namely Aβ(9–16)G110, (H-9GGEVHHQK16-NH2), Aβ(9–16)G213,14 (H-9GYEVGGQK16-NH2), and Aβ(9–16)G310,13,14 (H-9GGEVGGQK16-NH2), were manually synthesised in order to study Al binding to more specific amino acid residues. Both the peptides and the corresponding complexes with aluminium were comparatively investigated by mass spectrometry (MS), circular dichroism spectroscopy (CD), atomic force microscopy (AFM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR). Al–peptide molecular ions and Al-fragment ions were unambiguously identified in the MS and MS/MS spectra. AFM images showed dramatic changes in the film morphology of peptides upon Al binding. Our findings from the investigation of N-terminal 1-16 and even 9-16 normal and modified sequences of Aβ peptides suggest that they have the capability to be involved in aluminium ion binding associated with AD.

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Mercury and Alzheimer’s Disease: Hg(II) Ions Display Specific Binding to the Amyloid-β Peptide and Hinder Its Fibrillization

Cited by 29 publications

References 169 publications

Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation–inert complex

Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation–inert complex

Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation

Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

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