Journal Article

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

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

2013

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Aggregation / Algorithms / Alzheimer disease / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / amyloid / Amyloid - chemistry / Amyloid - metabolism / Amyloid beta-Peptides - chemistry / Amyloid beta-Peptides - metabolism / Amyloid beta-Peptides - pharmacology / Amyloids / Biological Sciences / Biophysics and Computational Biology / Cell aggregates / Cell Line, Tumor / Cell Survival - drug effects / cell viability / cytotoxicity / Humans / Isotope Labeling / Kinetics / Models, Chemical / Models, Molecular / Monomers / Neurons / neurotoxicity / Nucleation / Oligomers / Peptide Fragments - chemistry / Peptide Fragments - metabolism / Peptide Fragments - pharmacology / Plaque, Amyloid - chemistry / Plaque, Amyloid - metabolism / Polymerization / Protein Conformation / Protein Multimerization / radiolabeling / Solar fibrils / Viability