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New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding

The relative abundance of two main Abeta-peptide types with different lengths, Aβ40 and Aβ42, determines the severity of the Alzheimer’s disease progression. However, the factors responsible for different behavior patterns of these peptides in the amyloidogenesis process remain unknown. In this comp...

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Autores principales: Sulatskaya, Anna I., Rychkov, Georgy N., Sulatsky, Maksim I., Mikhailova, Ekaterina V., Melnikova, Nadezhda M., Andozhskaya, Veronika S., Kuznetsova, Irina M., Turoverov, Konstantin K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141448/
https://www.ncbi.nlm.nih.gov/pubmed/35628325
http://dx.doi.org/10.3390/ijms23105513
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author Sulatskaya, Anna I.
Rychkov, Georgy N.
Sulatsky, Maksim I.
Mikhailova, Ekaterina V.
Melnikova, Nadezhda M.
Andozhskaya, Veronika S.
Kuznetsova, Irina M.
Turoverov, Konstantin K.
author_facet Sulatskaya, Anna I.
Rychkov, Georgy N.
Sulatsky, Maksim I.
Mikhailova, Ekaterina V.
Melnikova, Nadezhda M.
Andozhskaya, Veronika S.
Kuznetsova, Irina M.
Turoverov, Konstantin K.
author_sort Sulatskaya, Anna I.
collection PubMed
description The relative abundance of two main Abeta-peptide types with different lengths, Aβ40 and Aβ42, determines the severity of the Alzheimer’s disease progression. However, the factors responsible for different behavior patterns of these peptides in the amyloidogenesis process remain unknown. In this comprehensive study, new evidence on Aβ40 and Aβ42 amyloid polymorphism was obtained using a wide range of experimental approaches, including custom-designed approaches. We have for the first time determined the number of modes of thioflavin T (ThT) binding to Aβ40 and Aβ42 fibrils and their binding parameters using a specially developed approach based on the use of equilibrium microdialysis, which makes it possible to distinguish between the concentration of the injected dye and the concentration of dye bound to fibrils. The binding sites of one of these modes located at the junction of adjacent fibrillar filaments were predicted by molecular modeling techniques. We assumed that the sites of the additional mode of ThT-Aβ42 amyloid binding observed experimentally (which are not found in the case of Aβ40 fibrils) are localized in amyloid clots, and the number of these sites could be used for estimation of the level of fiber clustering. We have shown the high tendency of Aβ42 fibers to form large clots compared to Aβ40 fibrils. It is probable that this largely determines the high resistance of Aβ42 amyloids to destabilizing effects (denaturants, ionic detergents, ultrasonication) and their explicit cytotoxic effect, which we have shown. Remarkably, cross-seeding of Aβ40 fibrillogenesis using the preformed Aβ42 fibrils changes the morphology and increases the stability and cytotoxicity of Aβ40 fibrils. The differences in the tendency to cluster and resistance to external factors of Aβ40 and Aβ42 fibrils revealed here may be related to the distinct role they play in the deposition of amyloids and, therefore, differences in pathogenicity in Alzheimer’s disease.
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spelling pubmed-91414482022-05-28 New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding Sulatskaya, Anna I. Rychkov, Georgy N. Sulatsky, Maksim I. Mikhailova, Ekaterina V. Melnikova, Nadezhda M. Andozhskaya, Veronika S. Kuznetsova, Irina M. Turoverov, Konstantin K. Int J Mol Sci Article The relative abundance of two main Abeta-peptide types with different lengths, Aβ40 and Aβ42, determines the severity of the Alzheimer’s disease progression. However, the factors responsible for different behavior patterns of these peptides in the amyloidogenesis process remain unknown. In this comprehensive study, new evidence on Aβ40 and Aβ42 amyloid polymorphism was obtained using a wide range of experimental approaches, including custom-designed approaches. We have for the first time determined the number of modes of thioflavin T (ThT) binding to Aβ40 and Aβ42 fibrils and their binding parameters using a specially developed approach based on the use of equilibrium microdialysis, which makes it possible to distinguish between the concentration of the injected dye and the concentration of dye bound to fibrils. The binding sites of one of these modes located at the junction of adjacent fibrillar filaments were predicted by molecular modeling techniques. We assumed that the sites of the additional mode of ThT-Aβ42 amyloid binding observed experimentally (which are not found in the case of Aβ40 fibrils) are localized in amyloid clots, and the number of these sites could be used for estimation of the level of fiber clustering. We have shown the high tendency of Aβ42 fibers to form large clots compared to Aβ40 fibrils. It is probable that this largely determines the high resistance of Aβ42 amyloids to destabilizing effects (denaturants, ionic detergents, ultrasonication) and their explicit cytotoxic effect, which we have shown. Remarkably, cross-seeding of Aβ40 fibrillogenesis using the preformed Aβ42 fibrils changes the morphology and increases the stability and cytotoxicity of Aβ40 fibrils. The differences in the tendency to cluster and resistance to external factors of Aβ40 and Aβ42 fibrils revealed here may be related to the distinct role they play in the deposition of amyloids and, therefore, differences in pathogenicity in Alzheimer’s disease. MDPI 2022-05-15 /pmc/articles/PMC9141448/ /pubmed/35628325 http://dx.doi.org/10.3390/ijms23105513 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sulatskaya, Anna I.
Rychkov, Georgy N.
Sulatsky, Maksim I.
Mikhailova, Ekaterina V.
Melnikova, Nadezhda M.
Andozhskaya, Veronika S.
Kuznetsova, Irina M.
Turoverov, Konstantin K.
New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
title New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
title_full New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
title_fullStr New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
title_full_unstemmed New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
title_short New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
title_sort new evidence on a distinction between aβ40 and aβ42 amyloids: thioflavin t binding modes, clustering tendency, degradation resistance, and cross-seeding
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141448/
https://www.ncbi.nlm.nih.gov/pubmed/35628325
http://dx.doi.org/10.3390/ijms23105513
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