A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways
A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways
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一种博弈论方法来破译淀粉样蛋白-β沿着竞争途径聚集的动态
DOI：
10.1101/581629
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发表时间：
2020
影响因子：
3.5
通讯作者：
Vaidya, A.
中科院分区：
文献类型：
--
作者：
Ghosh, P.;Rana, P.;Rangachari, V.;Saha, J.;Steen, E.;Vaidya, A.
淀粉样蛋白-β(Aβ)多肽的聚集是阿尔茨海默病(AD)的重要基础事件。Aβ聚集体，尤其是低分子量低聚物，是AD发病机制中的主要毒物。因此，人们对了解它们的形成和行为越来越感兴趣。在这篇文章中，我们利用我们先前建立的Aβ和脂肪酸(FA)之间异型相互作用的结果来研究FA浓度控制下的途径外聚集，以建立一个捕捉到这一机制的数学框架。我们的框架是基于博弈论的原理来定义和模拟Aβ聚集的竞争路径。结合详细的模拟和生物物理实验，我们的模型描述了在FA存在的情况下Aβ聚集机制中涉及的动力学因素，从而采用了多种途径。具体地说，我们的降阶计算表明，路径外或路径上聚集体的出现受到一组狭窄的速率常数的严格控制，人们可以改变这些参数来填充特定的低聚物种。这些模型与关于使用FA作为异型伙伴来调制时间参数的详细模拟和实验数据相一致。预测特定异型伴侣(如脂类)沿竞争路径的时空景观是模拟场景的第一步，在这种场景中，可以预测Aβ的特定“构象菌株”的产生。这一方法可能对破译淀粉样蛋白聚集和菌株产生的机制具有重要意义，这些机制在许多神经退行性疾病中普遍观察到。
Aggregation of amyloid-β(Aβ) peptides is a significant event that underpins Alzheimer's disease (AD). Aβaggregates, 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 Aβand 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 Aβaggregation 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 Aβaggregation 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 Aβcould 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.
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阿尔茨海默病 Aβ 聚集状态对仿生脂质囊泡渗透的影响。
DOI：
10.1021/la101581g
发表时间：
2010
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
--
作者：
Thomas L. Williams;I. J. Day;L. Serpell
通讯作者：
L. Serpell
阿尔茨海默氏β-淀粉样肽的替代聚集途径：内体 pH 值下的 Abeta 关联动力学。
影响因子：
5.6
作者：
P. Gorman;C. Yip;P. Fraser;A. Chakrabartty
通讯作者：
A. Chakrabartty
影响因子：
6.1
作者：
Gellermann, Gerald P.;Byrnes, Helga;Barghorn, Stefan
通讯作者：
Barghorn, Stefan
DOI：
10.1073/pnas.0911326107
发表时间：
2010-03-23
影响因子：
11.1
作者：
Dahms, Sven O.;Hoefgen, Sandra;Than, Manuel E.
通讯作者：
Than, Manuel E.
影响因子：
2.9
作者：
Dean DN;Pate KM;Moss MA;Rangachari V
通讯作者：
Rangachari V