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

The aggregation kinetics of Aβ1-40 peptide was characterized using a synergistic approach bya combination ofnuclear 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~20nm); ii) conversion of the HMWO into more compact Rh~10nm fibrils nuclei; iii) fast formation of additionalfibrils nucleithrough 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.&nbsp