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

• Published in: Journal of structural biology 2016-06, Vol.194 (3), p.404-414
• Main Authors: Dovidchenko, Nikita V., Glyakina, Anna V., Selivanova, Olga M., Grigorashvili, Elizaveta I., Suvorina, Mariya Yu, Dzhus, Ulyana F., Mikhailina, Alisa O., Shiliaev, Nikita G., Marchenkov, Victor V., Surin, Alexey K., Galzitskaya, Oxana V.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid - biosynthesis; Amyloid beta-Peptides - chemistry; Amyloid fibril; Aβ40 peptide; Aβ42 peptide; Electron microscopy; Escherichia coli; Models, Molecular; Oligomer; Peptide Fragments; Protein Folding; Secondary nucleation; Size of nucleus
• ISSN: 1047-8477; 1095-8657
• DOI: 10.1016/j.jsb.2016.03.020

In the presented paper, theoretical as well as electron microscopy and X-ray diffraction experimental approaches were employed for studding the process of Aβ amyloid formation. Using quantitative estimates of a number of monomers which form the nuclei of amyloid fibrils the sizes of folding nuclei of amyloid fibrils for Aβ40 and 42 have been determined for the first time. We have shown that the size of the primary nucleus of Aβ42 peptide fibrils corresponds to 3 monomers, the size of the secondary nucleus for this peptide is 2 monomers. Applying the same analysis to Aβ40 we conclude that the size of the primary nucleus is 2 monomers, and the size of the secondary nucleus is one monomer. Summation of our theoretical and experimental results has allowed us to propose a new model of the structural organization of amyloid fibrils. Our model suggests that the generation of fibrils takes place along the following simplified pathway: a monomer→a ring oligomer→a mature fibril consisting of ring oligomers. These data shed more light upon our understanding of what sizes of the oligomers could represent main targets for future therapies (tetramers for Aβ42 and trimers for Aβ40), and aid in the development of inhibitors of Aβ40 and 42 oligomer formation.