Department of Electronics and Tele-Communication Engineering, Jadavpur University, Kolkata, India.
College of Nanoscale Science, Nanobioscience Constellation, State University of New York Polytechnic Institute, Albany, NY, USA.
Int J Nanomedicine. 2018 May 25;13:3105-3128. doi: 10.2147/IJN.S152664. eCollection 2018.
In tauopathies such as Alzheimer's disease (AD), molecular changes spanning multiple subcellular compartments of the neuron contribute to neurodegeneration and altered axonal signaling. Computational modeling of end-to-end linked events benefit mechanistic analysis and can be informative to understand disease progression and accelerate development of effective therapies. In the calcium-amyloid beta model of AD, calcium ions that are an important regulator of neuronal function undergo dysregulated homeostasis that disrupts cargo loading for neurotrophic signaling along axonal microtubules (MTs). The aim of the present study was to develop a computational model of the neuron using a layered architecture simulation that enables us to evaluate the functionalities of several interlinked components in the calcium-amyloid beta model.
The elevation of intracellular calcium levels is modeled upon binding of amyloid beta oligomers (AβOs) to calcium channels or as a result of membrane insertion of oligomeric Aβ1-42 to form pores/channels. The resulting subsequent Ca disruption of dense core vesicle (DCV)-kinesin cargo loading and transport of brain-derived neurotrophic factor (BDNF) on axonal MTs are then evaluated. Our model applies published experimental data on calcium channel manipulation of DCV-BDNF and incorporates organizational complexity of the axon as bundled polar and discontinuous MTs. The interoperability simulation is based on the Institute of Electrical and Electronics Engineers standard association P1906.1 framework for nanoscale and molecular communication.
Our analysis provides new spatiotemporal insights into the end-to-end signaling events linking calcium dysregulation and BDNF transport and by simulation compares the relative impact of dysregulation of calcium levels by AβO-channel interactions, oligomeric Aβ1-42 pores/channel formation, and release of calcium by internal stores. The flexible platform of our model allows continued expansion of molecular details including mechanistic and morphological parameters of axonal cytoskeleton networks as they become available to test disease and treatment predictions.
The present model will benefit future drug studies on calcium homeostasis and dysregulation linked to measurable neural functional outcomes. The algorithms used can also link to other multiscale multi-cellular modeling platforms to fill in molecular gaps that we believe will assist in broadening and refining multiscale computational maps of neurodegeneration.
在神经tau 病（如阿尔茨海默病[AD]）中，跨越神经元多个亚细胞区室的分子变化导致神经退行性变和轴突信号改变。端到端连接事件的计算建模有利于机制分析，并有助于了解疾病进展和加速有效治疗药物的开发。在 AD 的钙-淀粉样蛋白β模型中，作为神经元功能重要调节剂的钙离子经历失调的内稳态，破坏沿着轴突微管（MT）的神经滋养信号的货物加载。本研究的目的是使用分层架构模拟开发神经元的计算模型，使我们能够评估钙-淀粉样蛋白β模型中几个相互关联组件的功能。
细胞内钙水平的升高是通过淀粉样蛋白β寡聚物（AβOs）与钙通道结合或寡聚 Aβ1-42 插入膜形成孔/通道来建模的。然后评估由此产生的致密核心囊泡（DCV）-驱动蛋白货物加载和脑源性神经营养因子（BDNF）在轴突 MT 上的运输的随后 Ca 破坏。我们的模型应用了关于钙通道操纵 DCV-BDNF 的已发表实验数据，并纳入了轴突作为捆绑的极性和不连续 MT 的组织复杂性。互操作模拟基于电气和电子工程师协会标准协会 P1906.1 纳米级和分子通信框架。
我们的分析提供了关于钙失调和 BDNF 运输端到端信号事件的新的时空见解，并通过模拟比较了 AβO-通道相互作用、寡聚 Aβ1-42 孔/通道形成和内部储存物释放引起的钙失调对钙调节的相对影响。我们模型的灵活平台允许继续扩展分子细节，包括轴突细胞骨架网络的机制和形态参数，因为它们可用于测试疾病和治疗预测。
本模型将有益于未来与可测量神经功能结果相关的钙动态平衡和失调的药物研究。使用的算法还可以链接到其他多尺度多细胞建模平台，以填补我们认为将有助于拓宽和细化神经退行性变多尺度计算图的分子空白。
