期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 24, 页码 9758-9763出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1218402110
关键词
chemical kinetics; molecular mechanisms; protein misfolding; neurodegeneration
资金
- Newman Foundation
- Schiff Foundation
- Kennedy Memorial Trust
- Swedish Research Council
- Linneaus Centre Organizing Molecular Matter
- Crafoord Foundation
- Royal Physiographic Society
- Nanometer Structure Consortium at Lund University
- Alzheimerfonden
- Danish Research Foundation
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/H003843/1] Funding Source: researchfish
- BBSRC [BB/H003843/1] Funding Source: UKRI
The generation of toxic oligomers during the aggregation of the amyloid-beta (A beta) peptide A beta 42 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 A beta 42 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 A beta 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 A beta 42 oligomers.
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