Conversion of non-fibrillar β-sheet oligomers into amyloid fibrils in Alzheimer’s disease amyloid peptide aggregation

Aβ(1–40) is one of the main components of the fibrils found in amyloid plaques, a hallmark of brains affected by Alzheimer’s disease. It is known that prior to the formation of amyloid fibrils in which the peptide adopts a well-ordered intermolecular β-sheet structure, peptide monomers associate forming low and high molecular weight oligomers. These oligomers have been previously described in electron microscopy, AFM, and exclusion chromatography studies. Their specific secondary structures however, have not yet been well established. A major problem when comparing aggregation and secondary structure determinations in concentration-dependent processes such as amyloid aggregation is the different concentration range required in each type of experiment. In the present study we used the dye Thioflavin T (ThT), Fourier-transform infrared spectroscopy, and electron microscopy in order to structurally characterize the different aggregated species which form during the Aβ(1–40) fibril formation process. A unique sample containing 90 μM peptide was used. The results show that oligomeric species which form during the lag phase of the aggregation kinetics are a mixture of unordered, helical, and intermolecular non-fibrillar β-structures. The number of oligomers and the amount of non-fibrillar β-structures grows throughout the lag phase and during the elongation phase these non-fibrillar β-structures are transformed into fibrillar (amyloid) β-structures, formed by association of high molecular weight intermediates.