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沿竞争途径聚集的动态
DOI：
10.1098/rsos.191814
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发表时间：
2020
影响因子：
3.5
通讯作者：
Vaidya, Ashwin
中科院分区：
文献类型：
--
作者：
Ghosh, Preetam;Rana, Pratip;Rangachari, Vijayaraghavan;Saha, Jhinuk;Steen, Edward;Vaidya, Ashwin
淀粉样蛋白-β(a β)肽的聚集是阿尔茨海默病（AD）的重要基础。a β聚集物，特别是低分子量低聚物，是AD发病的主要毒性因子。因此，人们对了解它们的形成和行为越来越感兴趣。在本文中，我们利用我们之前建立的a β和脂肪酸（FAs）之间的异型相互作用的结果来研究FA浓度控制下的通路外聚集，并建立一个数学框架来捕捉其机制。我们定义和模拟a β聚集的竞争通路的框架是基于博弈论的原则。结合详细的模拟和生物物理实验，我们的模型描述了在FAs存在下a β聚集的动力学机制，并采用多种途径。具体来说，我们的降阶计算表明，通路外或通路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寡聚物物种。这些模型与详细的模拟和实验数据一致，表明利用FA作为异型伙伴来调节时间参数。预测特定异型伴侣（如脂质）的竞争途径的时空景观是模拟a β特定“构象菌株”产生的情景的第一步。这种方法可能在解释淀粉样蛋白聚集和菌株产生的机制方面具有重要意义，这在许多神经退行性疾病中普遍存在。
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.