Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism

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  • Samuel I A Cohen, University of Cambridge, United Kingdom
  • Sara Linse, Lund University, Sweden
  • Leila M Luheshi, University of Cambridge, United Kingdom
  • Erik Hellstrand, Lund University, Sweden
  • Duncan A White, University of Cambridge, United Kingdom
  • Luke Rajah, University of Cambridge, United Kingdom
  • Daniel Otzen
  • Michele Vendruscolo, University of Cambridge, United Kingdom
  • Christopher M Dobson, University of Cambridge, United Kingdom
  • Tuomas P J Knowles, University of Cambridge, United Kingdom
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.
Original languageEnglish
JournalPNAS (Proceedings of the National Academy of Sciences of the United States of America)
Volume110
Issue24
Pages (from-to)9758-9763
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 23 May 2013

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