The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism
Open accessAbstract
The generation of toxic oligomers during the aggregation of the amyloid-β (Aβ) peptide Aβ42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer’s disease, but the molecular pathways that control pathological aggregation have proved challenging to identify. Here, we use a combination of kinetic studies, selective radiolabeling experiments, and cell viability assays to detect directly the rates of formation of both fibrils and oligomers and the resulting cytotoxic effects. Our results show that once a small but critical concentration of amyloid fibrils has accumulated, the toxic oligomeric species are predominantly formed from monomeric peptide molecules through a fibril-catalyzed secondary nucleation reaction, rather than through a classical mechanism of homogeneous primary nucleation. This catalytic mechanism couples together the growth of insoluble amyloid fibrils and the generation of diffusible oligomeric aggregates that are implicated as neurotoxic agents in Alzheimer’s disease. These results reveal that the aggregation of Aβ42 is promoted by a positive feedback loop that originates from the interactions between the monomeric and fibrillar forms of this peptide. Our findings bring together the main molecular species implicated in the Aβ aggregation cascade and suggest that perturbation of the secondary nucleation pathway identified in this study could be an effective strategy to control the proliferation of neurotoxic Aβ42 oligomers.
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Citations
Cites
Protein folding and misfolding
Dobson, C. M. (2003) · Nature · doi:10.1038/nature02261 · Cited by 4,791
Self-citationSoluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
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Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
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“(2005) 3D structure of Alzheimer’s amyloid-beta(1-42) fibrils.”
Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases
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Self-citationCorrelation Between Elevated Levels of Amyloid β-Peptide in the Brain and Cognitive Decline
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Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain
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Water-soluble Aβ(N-40, N-42) oligomers in normal and Alzheimer disease brains
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Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide
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“(2005) 3D structure of Alzheimer’s amyloid-beta(1-42) fibrils.”
Method
Cited by
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
Chiti, F., & Dobson, C. M. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-045115 · Cited by 2,629
Self-citationThe amyloid state and its association with protein misfolding diseases.
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Self-citationThe Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Self-citationThe Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease
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The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870
Metadata
- Authors
- Cohen, S. I. A., Linse, S., Luheshi, L. M., Hellstrand, E., White, D. A., Rajah, L., Otzen, D. E., Vendruscolo, M., Dobson, C. M., & Knowles, T. P. J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2013-05-23
- Volume
- 110
- Issue
- 24
- Pages
- 9758-9763
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2030325989
- Cited by
- 1,440
- References
- 10
- FWCI
- 61.00
- Type
- journal article
- Language
- en
- Open access
- green
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- Cohen, S. I. A., Linse, S., Luheshi, L. M., Hellstrand, E., White, D. A., Rajah, L., Otzen, D. E., Vendruscolo, M., Dobson, C. M., & Knowles, T. P. J. (2013). Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1218402110
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