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Cited by 52Alzheimer's disease research and treatmentsProtein Structure and DynamicsPrion Diseases and Protein Misfolding

Molecular Structure of Cu(II)-Bound Amyloid-β Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer’s Disease

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Abelein, Axel, Ciofi-Baffoni, Simone, Mörman, Cecilia, Kumar, Rakesh, Giachetti, Andrea, Piccioli, Mario, Biverstål, Henrik·2022·JACS Au
DOI 10.1021/jacsau.2c00438PMC PMC9709942
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Abstract

Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer's patients. Among the physiological transition metal ions, Cu(II) ions play an outstanding role since they can trigger production of neurotoxic reactive oxygen species. In contrast, structural insights into Cu(II) coordination of Aβ have been challenging due to the paramagnetic nature of Cu(II). Here, we employed specifically tailored paramagnetic NMR experiments to determine NMR structures of Cu(II) bound to monomeric Aβ. We found that monomeric Aβ binds Cu(II) in the N-terminus and combined with molecular dynamics simulations, we could identify two prevalent coordination modes of Cu(II). For these, we report here the NMR structures of the Cu(II)-bound Aβ complex, exhibiting heavy backbone RMSD values of 1.9 and 2.1 Å, respectively. Further, applying aggregation kinetics assays, we identified the specific effect of Cu(II) binding on the Aβ nucleation process. Our results show that Cu(II) efficiently retards Aβ fibrillization by predominately reducing the rate of fibril-end elongation at substoichiometric ratios. A detailed kinetic analysis suggests that this specific effect results in enhanced Aβ oligomer generation promoted by Cu(II). These results can quantitatively be understood by Cu(II) interaction with the Aβ monomer, forming an aggregation inert complex. In fact, this mechanism is strikingly similar to other transition metal ions, suggesting a common mechanism of action of retarding Aβ self-assembly, where the metal ion binding to monomeric Aβ is a key determinant.

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  • Aberrant copper binding to Aβ facilitates aggregation of oligomers and fibrils while simultaneously catalyzing ROS production.

    “Aberrant copper binding to Aβ facilitates the aggregation of oligomers and fibrils while simultaneously catalyzing ROS production [110].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [110]

    The Results and Discussion report increased Aβ oligomer generation with Cu(II), and the Introduction links copper reduction to ROS formation. But the Introduction and Concluding Remarks say Cu(II) retards fibril formation by inhibiting fibril-end elongation, rather than facilitating it. The paper also describes ROS formation as a possible consequence of copper reduction, not as a directly measured catalytic effect in this study. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Abelein, A., Ciofi-Baffoni, S., Mörman, C., Kumar, R., Giachetti, A., Piccioli, M., & Biverstål, H.
Affiliations
  • Karolinska Institutet (SE)
  • Magnetic Resonance Center and Department of Chemistry, University of Florence, Via Luigi Sacconi 6, Sesto Fiorentino50019 , Florence, Italy
  • Stockholm University (SE)
  • University of Florence (IT)
Corresponding author
  • Abelein, Axel
  • Biverstål, Henrik
ORCID
Venue
JACS Au
Publisher
American Chemical Society (ACS)
Published
2022-11-11
Volume
2
Issue
11
Pages
2571-2584
ISSN
2691-3704 (ISSN-L)
DOI
10.1021/jacsau.2c00438
PMC
PMC9709942
OpenAlex
W4308921409
Cited by
52
References
7
Citations by year
2026: 10 · 2025: 13 · 2024: 14 · 2023: 14 · 2022: 1
FWCI
6.34
Type
journal article
Language
en
Open access
Licence
Locations
  • JACS Au (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Florence Research (University of Florence) (submittedVersion, cc-by)
Funders
  • Svenska Forskningsr?det Formas
  • Stiftelsen Sigurd and Elsa Goljes Minne
  • Vetenskapsr?det
  • Svenska S?llskapet f?r Medicinsk Forskning
  • Magnus Bergvalls Stiftelse
  • Petrus och Augusta Hedlunds Stiftelse
  • ?ke Wiberg Stiftelse
  • Horizon 2020 Framework Programme (101017567, 101046203, 2020-02905/EC, 643417)
  • Loo och Hans Ostermans Stiftelse f?r Medicinsk Forskning
  • Foundation for Geriatric Diseases KI
  • KI Research Foundation
  • ?hlen Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
amyloid-beta, copper(II) binding, metal coordination, nucleation, oligomerization, Alzheimer's disease, paramagnetic NMR, coordination modes

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