Dissection of the key steps of amyloid-β peptide 1–40 fibrillogenesis

• Published in: International journal of biological macromolecules 2020-12, Vol.164, p.2240-2246
• Main Authors: Leite, José P., Gimeno, Ana, Taboada, Pablo, Jiménez-Barbero, Jesús J., Gales, Luís
• Format: Article
• Language: English
• Subjects: Aggregation kinetics; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - chemistry; Amyloid-β peptide; Amyloid-β peptide oligomers; Aβ1–40; Benzothiazoles - chemistry; Dissection; Fluorescence; Kinetics; Microscopy, Electron, Transmission - methods; Nucleation; Peptide Fragments - chemistry; Protein Multimerization
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2020.08.023

The aggregation kinetics of Aβ1–40 peptide was characterized using a synergistic approach by a combination of nuclear magnetic resonance, thioflavin-T fluorescence, transmission electron microscopy and dynamic light scattering. A major finding is the experimental detection of high molecular weight oligomers (HMWO) that converts into fibrils nuclei. Our observations are consistent with a mechanism of Aβ1–40 fibrillogenesis that includes the following key steps: i) slow formation of HMWO (Rh ~ 20 nm); ii) conversion of the HMWO into more compact Rh ~ 10 nm fibrils nuclei; iii) fast formation of additional fibrils nuclei through fibril surface catalysed processes; and iv) growth of fibrils by addition of soluble Aβ species. Moreover, NMR diffusion experiments show that at 37 °C soluble Aβ1–40 remains intrinsically disordered and mostly in monomeric form despite evidences of the presence of dimers and/or other small oligomers. A mathematical model is proposed to simulate the aggregation kinetics of Aβ1–40.