Zn(II)‐ and Cu(II)‐induced non‐fibrillar aggregates of amyloid‐β (1–42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators
Abstract
Aggregation of amyloid-beta (Abeta) peptides is a central phenomenon in Alzheimer's disease. Zn(II) and Cu(II) have profound effects on Abeta aggregation; however, their impact on amyloidogenesis is unclear. Here we show that Zn(II) and Cu(II) inhibit Abeta(42) fibrillization and initiate formation of non-fibrillar Abeta(42) aggregates, and that the inhibitory effect of Zn(II) (IC(50) = 1.8 micromol/L) is three times stronger than that of Cu(II). Medium and high-affinity metal chelators including metallothioneins prevented metal-induced Abeta(42) aggregation. Moreover, their addition to preformed aggregates initiated fast Abeta(42) fibrillization. Upon prolonged incubation the metal-induced aggregates also transformed spontaneously into fibrils, that appear to represent the most stable state of Abeta(42). H13A and H14A mutations in Abeta(42) reduced the inhibitory effect of metal ions, whereas an H6A mutation had no significant impact. We suggest that metal binding by H13 and H14 prevents the formation of a cross-beta core structure within region 10-23 of the amyloid fibril. Cu(II)-Abeta(42) aggregates were neurotoxic to neurons in vitro only in the presence of ascorbate, whereas monomers and Zn(II)-Abeta(42) aggregates were non-toxic. Disturbed metal homeostasis in the vicinity of zinc-enriched neurons might pre-dispose formation of metal-induced Abeta aggregates, subsequent fibrillization of which can lead to amyloid formation. The molecular background underlying metal-chel…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Zn2+ promotes formation of nonfibrillar aggregates.
“Several studies showed that Zn2+ promotes formation of nonfibrillar aggregates,16,29–31 yet conflicting results have been reported for the Cu2+-mediated Aβ aggregation.”
From The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity (2013) · cites this paper as [31]
Zn2+ causes rapid formation of nonfibrillar aggregates.
“For example, while Zn2+ was shown to cause rapid formation of nonfibrillar aggregates,41”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [41]
The role of metal ions in Aβ42 aggregation remains unclear and only few reports are available in the literature.
“However, the role of metal ions in Aβ42 aggregation still remains unclear and only few reports are available in the literature.37–41”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [41]
Both Cu2+ and Zn2+ ions lead to a reduced ThT fluorescence, due to emission quenching by the paramagnetic Cu2+ ions or Zn2+-induced formation of non-fibrillar Aβ aggregates.
“In addition, both Cu2+ and Zn2+ ions lead to a reduced ThT fluorescence, due to emission quenching by the paramagnetic Cu2+ ions or Zn2+-induced formation of non-fibrillar Aβ aggregetes.41,88”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [41]
Cites
Copper, iron and zinc in Alzheimer's disease senile plaques
Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L., & Markesbery, W. R. (1998) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(98)00092-6 · Cited by 2,120 · see citing works
Aβ Oligomers – a decade of discovery
Walsh, D. M., & Selkoe, D. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04426.x · Cited by 1,938 · see citing works
Rapid induction of Alzheimer A beta amyloid formation by zinc
Bush, A., Pettingell, W., Multhaup, G., d Paradis, M., Vonsattel, J., Gusella, J., Beyreuther, K., Masters, C., & Tanzi, R. (1994) · Science · doi:10.1126/science.8073293 · Cited by 1,522 · see citing works
Cherny, R. A., Atwood, C. S., Xilinas, M. E., Gray, D. N., Jones, W. D., McLean, C. A., Barnham, K. J., Volitakis, I., Fraser, F. W., Kim, Y.-S., et al. (2001) · Neuron · doi:10.1016/s0896-6273(01)00317-8 · Cited by 1,447 · see citing works
Atwood, C. S., Moir, R. D., Huang, X., Scarpa, R. C., Bacarra, N. M. E., Romano, D. M., Hartshorn, M. A., Tanzi, R. E., & Bush, A. I. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.21.12817 · Cited by 1,009 · see citing works
Exogenous Induction of Cerebral ß-Amyloidogenesis Is Governed by Agent and Host
Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A. L., et al. (2006) · Science · doi:10.1126/science.1131864 · Cited by 971 · see citing works
Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity
Huang, X., Cuajungco, M. P., Atwood, C. S., Hartshorn, M. A., Tyndall, J. D. A., Hanson, G. R., Stokes, K. C., Leopold, M., Multhaup, G., Goldstein, L. E., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.37111 · Cited by 762 · see citing works
Aqueous Dissolution of Alzheimer's Disease Aβ Amyloid Deposits by Biometal Depletion
Cherny, R. A., Legg, J. T., McLean, C. A., Fairlie, D. P., Huang, X., Atwood, C. S., Beyreuther, K., Tanzi, R. E., Masters, C. L., & Bush, A. I. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.33.23223 · Cited by 482 · see citing works
Metals and Alzheimer's disease
Adlard, P. A., & Bush, A. I. (2006) · Journal of Alzheimer's Disease · doi:10.3233/jad-2006-102-303 · Cited by 324 · see citing works
White, A. R., Du, T., Laughton, K. M., Volitakis, I., Sharples, R. A., Xilinas, M. E., Hoke, D. E., Holsinger, R. M. D., Evin, G., Cherny, R. A., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602487200 · Cited by 284 · see citing works
New Insights on How Metals Disrupt Amyloid β-Aggregation and Their Effects on Amyloid-β Cytotoxicity
Yoshiike, Y., Tanemura, K., Murayama, O., Akagi, T., Murayama, M., Sato, S., Sun, X., Tanaka, N., & Takashima, A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010706200 · Cited by 244 · cited 2× · see citing works
“Later it was found that the metal-induced Ab aggregates are predominantly nonfibrillar (Yoshiike et al. 2001; Raman et al. 2005), however, enhanced fibril formation in the presence of metal ions has also been observed (Klug et al. 2003; Ricchelli et al. 2005).”
BackgroundResult
Flagged first, then by citations
Cited by
Sorted by citations
Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide
Sharma, A. K., Pavlova, S. T., Kim, J., Finkelstein, D., Hawco, N. J., Rath, N. P., Kim, J., & Mirica, L. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja210588m · Cited by 202 · see citing works
Sarell, C. J., Wilkinson, S. R., & Viles, J. H. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.171355 · Cited by 199 · see citing works
Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease
Cristóvão, J. S., Santos, R., & Gomes, C. M. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/9812178 · Cited by 146 · see citing works
The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity
Sharma, A. K., Pavlova, S. T., Kim, J., Kim, J., & Mirica, L. M. (2013) · Metallomics · doi:10.1039/c3mt00161j · Cited by 135 · see citing works
Zhang, Y., Rempel, D. L., Zhang, J., Sharma, A. K., Mirica, L. M., & Gross, M. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309175110 · Cited by 118 · see citing works
Medical Plants and Nutraceuticals for Amyloid-β Fibrillation Inhibition
Witter, S., Witter, R., Vilu, R., & Samoson, A. (2018) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-180066 · Cited by 25 · see citing works
- Authors
- Tõugu, V., Karafin, A., Zovo, K., Chung, R. S., Howells, C., West, A. K., & Palumaa, P.
- Affiliations
- Tallinn University of Technology (EE)
- University of Tasmania (AU)
- Corresponding author
- Tõugu, Vello
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2009-09
- Volume
- 110
- Issue
- 6
- Pages
- 1784-1795
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2057436204
- Cited by
- 181
- References
- 11
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 12 · 2021: 8 · 2020: 13 · 2019: 15 · 2018: 12 · 2017: 13 · 2016: 18 · 2015: 16 · 2014: 9 · 2013: 12 · 2012: 20
- FWCI
- 10.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- eCite Digital Repository (University of Tasmania) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- Eesti Teadusfondi
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta 42, zinc(II), copper(II), metal-induced aggregation, amyloid fibril formation, metal chelators, metallothionein, Alzheimer's disease, neurotoxicity, vitamin C, metal homeostasis
- MeSH terms
- Metallothionein 3, Alanine, Amyloid, Animals, Cells, Cultured, Cerebral Cortex, Chelating Agents, Copper, Dose-Response Relationship, Drug, Histidine, Mutation, Nerve Tissue Proteins, Neurons, Peptide Fragments, Thiazoles, Time Factors, Zinc, Amyloid beta-Peptides, Microscopy, Electron, Transmission, Rats, Benzothiazoles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
