One of the possible mechanisms of amyloid fibrils formation based on the sizes of primary and secondary folding nuclei of Aβ40 and Aβ42

Rosetta Stone for Amyloid Fibrils: The Key Role of Ring-Like Oligomers in Amyloidogenesis

“…To support this model, one can note the similar width of A␤ 1-42 and A␤ 1-40 oligomers (Fig. 2); but A␤ 1-42 fibrils are slightly wider than A␤ 1-40 fibrils due to lower orderliness of the ring-like oligomers in A␤ 1-42 fibrils [36,38]. As a direct consequence of the square structure, the fibril crosssection must have a hole in the center, which must be larger (∼3 nm) than that inside the triangular structure (∼1 nm).…”

“…A number of models has been proposed for the process of assembling of amyloid fibrils, in which the interaction of oligomer particles in different ways leads to formation of elongated polymers of various amyloid proteins [18,[25][26][27][28][29]. Our own studies of different amyloidogenic proteins (insulin, A␤ peptides, and their fragments, amyloidogenic fragments of Bgl2 protein) show that at the beginning of fibril formation a large number of oligomer ring-like structures is observed as well as a small number of short thin fibrils with a diameter comparable to that of oligomers [36][37][38][39][40]. As the time of incubation increases, the fraction of oligomer particles decreases, fibrils grow to several micrometers in length, and fibrils of different morphologies are formed.…”

“…In the cross section of a fibril, such packing is seen as a ring structure, the internal diameter of the ring being about 15-20Å [70]. Surprisingly, it is possible to see exactly the same morphology of A␤ peptide fibrils using the EM method [36][37][38]44]. However, the knowledge accumulated during the recent years and the remaining unsolved problems of the structure organization as well as our data on amyloid peptides and their fragments allow us to propose another view on the process of fibrillogenesis, and the structural organization of amyloid fibrils.…”

“…If the ring oligomers interact with each other side-by-side, slightly overlapping each other, then ribbons of different widths (GluNB) [40], bundles of different diameters (AspNB) [40] and films (A␤ [16][17][18][19][20][21][22][23][24][25] ) [72] are formed. In the chaotic interaction of ring oligomers fibrils with a rough surface are formed (A␤ 42 R) [36,38].…”

“…Nonetheless, every peptide exhibits some peculiarities upon oligomer formation. The diameter of oligomers, their height and internal diameter of the ring, as well as the number and way of packing of molecules within oligomers, can vary [36,[38][39][40]. It becomes evident how important it is for correct interpretation of the experimental data obtained with EM methods to consider the role of X-ray diffraction (sample preparation and analysis of the diffraction patterns), solid-state nuclear magnetic resonance (ssNMR), as well as final revision of the results using the methods of theoretical biophysics and bioinformatics.…”