Mathematics Department, Norwich University, Northfield, Vermont, United States of America.
Chemistry and Biochemistry Department, Norwich University, Northfield, Vermont, United States of America.
PLoS One. 2018 Aug 22;13(8):e0202503. doi: 10.1371/journal.pone.0202503. eCollection 2018.
The accumulation of Alzheimer's disease (AD) associated Amyloid beta (Aβ) oligomers can trigger aberrant intracellular calcium (Ca2+) levels by disrupting the intrinsic Ca2+ regulatory mechanism within cells. These disruptions can cause changes in homeostasis levels that can have detrimental effects on cell function and survival. Although studies have shown that Aβ can interfere with various Ca2+ fluxes, the complexity of these interactions remains elusive. We have constructed a mathematical model that simulates Ca2+ patterns under the influence of Aβ. Our simulations shows that Aβ can increase regions of mixed-mode oscillations leading to aberrant signals under various conditions. We investigate how Aβ affects individual flux contributions through inositol triphosphate (IP3) receptors, ryanodine receptors, and membrane pores. We demonstrate that controlling for the ryanodine receptor's maximal kinetic reaction rate may provide a biophysical way of managing aberrant Ca2+ signals. The influence of a dynamic model for IP3 production is also investigated under various conditions as well as the impact of changes in membrane potential. Our model is one of the first to investigate the effects of Aβ on a variety of cellular mechanisms providing a base modeling scheme from which further studies can draw on to better understand Ca2+ regulation in an AD environment.
阿尔茨海默病（AD）相关的淀粉样蛋白β（Aβ）寡聚体的积累可以通过破坏细胞内固有钙（Ca2+）调节机制来触发异常的细胞内钙（Ca2+）水平。这些破坏会导致内稳态水平的变化，从而对细胞功能和存活产生不利影响。尽管研究表明 Aβ 可以干扰各种 Ca2+流，但这些相互作用的复杂性仍然难以捉摸。我们构建了一个数学模型来模拟 Aβ 影响下的 Ca2+模式。我们的模拟表明，Aβ 可以增加混合模式振荡的区域，从而在各种条件下导致异常信号。我们研究了 Aβ 如何通过肌醇三磷酸（IP3）受体、兰尼碱受体和膜孔影响单个通量贡献。我们证明，控制兰尼碱受体的最大动力学反应速率可能为管理异常 Ca2+信号提供一种生物物理方法。还研究了各种条件下 IP3 产生的动态模型的影响以及膜电位变化的影响。我们的模型是第一个研究 Aβ 对各种细胞机制影响的模型之一，为进一步研究提供了基础建模方案，以更好地理解 AD 环境中的 Ca2+调节。
