Rapid Conversion of Amyloid-Beta 1-40 Oligomers to Mature Fibrils through a Self-Catalytic Bimolecular Process Morel, Bertrand Carrasco Jiménez, María Paz Jurado, Samuel Conejero Lara, Francisco Oligomerization Aggregation kinetics Fibrillation Mechanism Catalysis Abeta The formation of fibrillar aggregates of the amyloid beta peptide (Aβ) in the brain is one of the hallmarks of Alzheimer’s disease (AD). A clear understanding of the different aggregation steps leading to fibrils formation is a keystone in therapeutics discovery. In a recent study, we showed that Aβ40 and Aβ42 form dynamic micellar aggregates above certain critical concentrations, which mediate a fast formation of more stable oligomers, which in the case of Aβ40 are able to evolve towards amyloid fibrils. Here, using different biophysical techniques we investigated the role of different fractions of the Aβ aggregation mixture in the nucleation and fibrillation steps. We show that both processes occur through bimolecular interplay between low molecular weight species (monomer and/or dimer) and larger oligomers. Moreover, we report here a novel self-catalytic mechanism of fibrillation of Aβ40, in which early oligomers generate and deliver low molecular weight amyloid nuclei, which then catalyze the rapid conversion of the oligomers to mature amyloid fibrils. This fibrillation catalytic activity is not present in freshly disaggregated low-molecular weight Aβ40 and is, therefore, a property acquired during the aggregation process. In contrast to Aβ40, we did not observe the same self-catalytic fibrillation in Aβ42 spheroidal oligomers, which could neither be induced to fibrillate by the Aβ40 nuclei. Our results reveal clearly that amyloid fibrillation is a multi-component process, in which dynamic collisions between different interacting species favor the kinetics of amyloid nucleation and growth. 2021-07-01T11:47:49Z 2021-07-01T11:47:49Z 2021 info:eu-repo/semantics/article Morel, B.; Carrasco-Jiménez, M.P.; Jurado, S.; Conejero-Lara, F. Rapid Conversion of Amyloid-Beta 1-40 Oligomers to Mature Fibrils through a Self-Catalytic Bimolecular Process. Int. J. Mol. Sci. 2021, 22, 6370. https://doi.org/10.3390/ ijms22126370 http://hdl.handle.net/10481/69463 10.3390/ijms22126370 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI