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A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways
Aggregation of amyloid-β (Aβ) peptides is a significant event that underpins Alzheimer's disease (AD). Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and beha...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211858/ https://www.ncbi.nlm.nih.gov/pubmed/32431878 http://dx.doi.org/10.1098/rsos.191814 |
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author | Ghosh, Preetam Rana, Pratip Rangachari, Vijayaraghavan Saha, Jhinuk Steen, Edward Vaidya, Ashwin |
author_facet | Ghosh, Preetam Rana, Pratip Rangachari, Vijayaraghavan Saha, Jhinuk Steen, Edward Vaidya, Ashwin |
author_sort | Ghosh, Preetam |
collection | PubMed |
description | Aggregation of amyloid-β (Aβ) peptides is a significant event that underpins Alzheimer's disease (AD). Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behaviour. In this paper, we use our previously established results on heterotypic interactions between Aβ and fatty acids (FAs) to investigate off-pathway aggregation under the control of FA concentrations to develop a mathematical framework that captures the mechanism. Our framework to define and simulate the competing on- and off-pathways of Aβ aggregation is based on the principles of game theory. Together with detailed simulations and biophysical experiments, our models describe the dynamics involved in the mechanisms of Aβ aggregation in the presence of FAs to adopt multiple pathways. Specifically, our reduced-order computations indicate that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constants, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on using FA as a heterotypic partner to modulate the temporal parameters. Predicting spatio-temporal landscape along competing pathways for a given heterotypic partner such as lipids is a first step towards simulating scenarios in which the generation of specific ‘conformer strains’ of Aβ could be predicted. This approach could be significant in deciphering the mechanisms of amyloid aggregation and strain generation, which are ubiquitously observed in many neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-7211858 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-72118582020-05-19 A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways Ghosh, Preetam Rana, Pratip Rangachari, Vijayaraghavan Saha, Jhinuk Steen, Edward Vaidya, Ashwin R Soc Open Sci Mathematics Aggregation of amyloid-β (Aβ) peptides is a significant event that underpins Alzheimer's disease (AD). Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behaviour. In this paper, we use our previously established results on heterotypic interactions between Aβ and fatty acids (FAs) to investigate off-pathway aggregation under the control of FA concentrations to develop a mathematical framework that captures the mechanism. Our framework to define and simulate the competing on- and off-pathways of Aβ aggregation is based on the principles of game theory. Together with detailed simulations and biophysical experiments, our models describe the dynamics involved in the mechanisms of Aβ aggregation in the presence of FAs to adopt multiple pathways. Specifically, our reduced-order computations indicate that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constants, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on using FA as a heterotypic partner to modulate the temporal parameters. Predicting spatio-temporal landscape along competing pathways for a given heterotypic partner such as lipids is a first step towards simulating scenarios in which the generation of specific ‘conformer strains’ of Aβ could be predicted. This approach could be significant in deciphering the mechanisms of amyloid aggregation and strain generation, which are ubiquitously observed in many neurodegenerative diseases. The Royal Society 2020-04-29 /pmc/articles/PMC7211858/ /pubmed/32431878 http://dx.doi.org/10.1098/rsos.191814 Text en © 2020 The Authors. http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/http://creativecommons.org/licenses/by/4.0/Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. |
spellingShingle | Mathematics Ghosh, Preetam Rana, Pratip Rangachari, Vijayaraghavan Saha, Jhinuk Steen, Edward Vaidya, Ashwin A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways |
title | A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways |
title_full | A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways |
title_fullStr | A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways |
title_full_unstemmed | A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways |
title_short | A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways |
title_sort | game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways |
topic | Mathematics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211858/ https://www.ncbi.nlm.nih.gov/pubmed/32431878 http://dx.doi.org/10.1098/rsos.191814 |
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