Copper Abolishes the β-Sheet Secondary Structure of Preformed Amyloid Fibrils of Amyloid-β42
Open accessAbstract
The observation of the co-deposition of metals and amyloid-beta(42) (Abeta(42)) in brain tissue in Alzheimer's disease prompted myriad investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric Abeta(12) and upon precipitation of the copper-peptide complex thereby prevents Abeta(42) from adopting a beta-sheet secondary structure. Copper is also bound by beta-sheet conformers of Abeta(42), and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar Abeta(42) with, for example, a 20-fold excess of the metal resulting in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of Abeta(42). The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer's disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the beta-sheet secondary structure of pre-formed, aged amyloid fibrils of Abeta(42). Copper may protect against the presence of beta-sheets of Abeta(42) in vivo, and its binding by fibrillar Abeta(42) could have implications for Alzheimer's disease therapy.
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In inhibition experiments, reduced ThT fluorescence was observed for Cu2+- and Zn2+-containing fibrils.
“In inhibition experiments, a reduced ThT fluorescence was observed for the Cu2+- and Zn2+-containing fibrils, as reported previously (Figure 6).21,49,50”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [50]
The Results report reduced ThT fluorescence after Cu(II) was added to preformed Aβ42 aggregates, and the Methods describe those assays. The paper does not report a corresponding Zn(II) result; its experiments tested copper, including with aggregates formed in the presence of aluminum. Thus this source supports the copper part of the claim, but not the zinc part. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe decreased ThT fluorescence in the presence of Cu2+ can be accounted for by less fibril formation, although quenching by paramagnetic Cu2+ could also be involved.
“A decreased ThT fluorescence32,36 in presence of Cu2+ ions can be accounted for by less fibril formation, although a quenching of fluorescence by the paramagnetic Cu2+ ions could also be involved.47”
From The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity (2013) · cites this paper as [36]
Citation 47 is attached to the possibility that paramagnetic Cu2+ quenches ThT fluorescence. The Discussion (page unavailable) attributes the decrease to changes in preformed fibrils and reports no evidence about paramagnetic quenching; a search for quenching and paramagnetism found no passage addressing that possibility. (LLM, conf=0.76)
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ResultFurther insight into the role of metals in amyloid formation by IAPP1-37 and ProIAPP1-48
Mold, M. J., Bunrat, C., Goswami, P., Roberts, A. N., Roberts, C. F., Taylor, N., Taylor, H. K., Wu, L., Fraser, P. E., & Exley, C. (2015) · journal of Diabetes Research and Clinical Metabolism · doi:10.7243/2050-0866-4-4 · Cited by 8 · see citing works
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Self-citationNMR probing of copper–amyloid β1–16 interactions and self-assembly
Sunanda, P., Raghothama, S., Palempalli, U. M. D., & Krishnarjuna, B. (2024) · Academia Biology · doi:10.20935/acadbiol7451
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- Authors
- House, E., Mold, M., Collingwood, J., Baldwin, A., Goodwin, S., & Exley, C.
- Affiliations
- Keele University (GB)
- University of Warwick (GB)
- Corresponding author
- Exley, Christopher
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2009-11-12
- Volume
- 18
- Issue
- 4
- Pages
- 811-817
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC2857508
- OpenAlex
- W1907997235
- Cited by
- 45
- References
- 18
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 4 · 2012: 7
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Engineering and Physical Sciences Research Council (EP/D066654/1)
- National Institute of Neurological Disorders and Stroke (R21NS060304)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- copper, amyloid-beta 42
- MeSH terms
- Alzheimer Disease, Amyloid, Birefringence, Congo Red, Copper, Fluorescent Dyes, Humans, Peptide Fragments, Peptides, Thiazoles, Amyloid beta-Peptides, Protein Structure, Secondary, Microscopy, Electron, Transmission, Benzothiazoles
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