Copper prevents amyloid-β1–42 from forming amyloid fibrils under near-physiological conditions in vitro

Mold, Matthew; Ouro-Gnao, Larissa; Wieckowski, Beata M.; Exley, Christopher

doi:10.1038/srep01256

Cited by 94 publications

(92 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…-induced inhibition of Aβ 42 aggregation (29). The final concentration of aggregates as well as the fibril morphology in the concentration range of 0-2.5 μM Zn 2+ is about the same, as monitored by the ThT end-point fluorescence (Fig.…”

Section: +mentioning

confidence: 83%

Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation

Abelein

Gräslund

Danielsson

2015

Proc. Natl. Acad. Sci. U.S.A.

105

154

View full text Add to dashboard Cite

Metal ions have emerged to play a key role in the aggregation process of amyloid β (Aβ) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic Aβ-Zn 2+ binding features as well as how Zn 2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn 2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc Aβ 40 aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn 2+ , the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn 2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn 2+ ion, forming a marginally stable, short-lived folded Aβ 40 species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded Aβ 40 -Zn 2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for Aβ 40 .Alzheimer's disease | amyloid beta peptide | aggregation kinetics | zinc ion interactions | NMR relaxation

show abstract

Section: +mentioning

confidence: 83%

Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation

Abelein

Gräslund

Danielsson

2015

Proc. Natl. Acad. Sci. U.S.A.

105

154

View full text Add to dashboard Cite

show abstract

“…A previous study on IAPP suggested that seeding abolished a lag phase in amyloid formation without influencing total amyloid formation [14] and we observed something similar for ProIAPP herein. However, 'lag' phases in amyloid formation are rarely observed under-near physiological conditions [4,15] and what we observed were increases in the rate of formation of β sheets of amyloid which also occurred, if to a lesser extent, following sham seeding. The latter are rarely used controls in previous studies on amyloid seeding.…”

Section: Seeded Aggregation Of Proiappmentioning

confidence: 71%

Further insight into the role of metals in amyloid formation by IAPP1-37 and ProIAPP1-48

Mold¹,

Bunrat²,

Goswami³

et al. 2015

J Diab Res Clin Met

Self Cite

View full text Add to dashboard Cite

Background: IAPP 1-37 and ProIAPP 1-48 are amyloidogenic peptides implicated in β-cell death in diabetes. Interactions with metals may be involved in both the cytotoxicity of these peptides and their deposition as amyloids associated with diabetes-related pathologies. Methods: We have used the complementary methods of thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM) to investigate the role of seeds and specifically metal-peptide seeds in accelerating amyloid formation by ProIAPP. In addition we have used these complementary methods alongside dynamic light scattering (DLS) to observe the dynamics of IAPP amyloid formation during the earliest phase of peptide aggregation. Results: Seeding universally resulted in an acceleration of amyloid formation, as indicated by increased ThT fluorescence, over the shorter term (minutes) while having no influence upon total amyloid deposits (no differences in ThT fluorescence) over many days. Only copper-peptide seeds were ineffective in accelerating amyloid formation above that observed for sham seeds (no peptide). Different seeding environments resulted in amyloid deposits of different fibrillar and non-fibrillar morphologies following longer term incubations regardless of the uniform nature of the respective measurements of ThT fluorescence. The aggregation dynamics of IAPP, mimicking its secretion into extracellular milieus, were complex and suggested that while metals at equimolar, generally increased rates of aggregation, with the possible exception of Cu(II), the range of sub-micron and micron-sized particles observed were not easily explained by either measurement of ThT fluorescence or imaging by TEM. Conclusions: Seeding may be significant in accelerating the formation of amyloid and in influencing the final morphologies of deposited amyloids but not in determining the total deposits of amyloid. It was of interest that copper-peptide seeds did not accelerate amyloid formation in the shorter term and this could indicate an incompatible seeding morphology due to copper? This first attempt to monitor aggregation dynamics of IAPP over only minutes has shown direct impact of metals on peptide particle size which could have implications for the cytotoxicity of IAPP in diabetes.

show abstract

“…Densitometry analysis revealed that 94% of the original fluorescence intensity of GFPdopa could be recovered with EDTA treatment. The copper dissociation constant of GFPdopa was shown to be 5.6 mM, which makes it relevant for Cu 2+ detection under certain disease conditions [55][56][57] and in environmental applications.…”

Section: Review Molecular Biosystemsmentioning

confidence: 99%

Expanding the chemistry of fluorescent protein biosensors through genetic incorporation of unnatural amino acids

Niu

Guo

2013

Mol. BioSyst.

View full text Add to dashboard Cite

Copper prevents amyloid-β1–42 from forming amyloid fibrils under near-physiological conditions in vitro

Cited by 94 publications

References 35 publications

Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation

Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation

Further insight into the role of metals in amyloid formation by IAPP1-37 and ProIAPP1-48

Expanding the chemistry of fluorescent protein biosensors through genetic incorporation of unnatural amino acids

Contact Info

Product

Resources

About