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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | White, Duncan A. Vendruscolo, Michele Dobson, Christopher M. Otzen, Daniel E. Rajah, Luke Knowles, Tuomas P. J. Cohen, Samuel I. A. Luheshi, Leila M. Linse, Sara Hellstrand, Erik |
| Description | Author Affiliation: Cohen SI ( Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.); |
| Abstract | The generation of toxic oligomers during the aggregation of the amyloid-ß (Aß) peptide Aß42 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 Aß42 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 Aß 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 Aß42 oligomers. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 24 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-06-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Amyloid Beta-Peptides Chemistry Amyloid Peptide Fragments Plaque, Amyloid Protein Multimerization Algorithms Alzheimer Disease Metabolism Pathology Pharmacology Cell Line, Tumor Cell Survival Drug Effects Isotope Labeling Kinetics Models, Chemical Models, Molecular Polymerization Protein Conformation Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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