Quantifying the dose-dependent impact of intracellular amyloid beta in a mathematical model of calcium regulation in xenopus oocyte

Alzheimer's disease (AD) is a devastating illness affecting over 40 million people worldwide. Intraneuronal rise of amyloid beta in its oligomeric forms (iA beta Os), has been linked to the pathogenesis of AD by disrupting cytosolic Ca2+ homeostasis. However, the specific mechanisms of action are still under debate and intense effort is ongoing to improve our understanding of the crucial steps involved in the mechanisms of A beta Os toxicity. We report the development of a mathematical model describing a proposed mechanism by which stimulation of Phospholipase C (PLC) by iA beta O, triggers production of IP3 with consequent abnormal release of Ca2+ from the endoplasmic reticulum (ER) through activation of IP3 receptor (IP3R) Ca2+ channels. After validating the model using experimental data, we quantify the effects of intracellular rise in iA beta Os on model solutions. Our model validates a dose-dependent influence of iA beta Os on IP3-mediated Ca2+ signaling. We investigate Ca2+ signaling patterns for small and large iA beta Os doses and study the role of various parameters on Ca2+ signals. Uncertainty quantification and partial rank correlation coefficients are used to better understand how the model behaves under various parameter regimes. Our model predicts that iA beta O alter IP3R sensitivity to IP3 for large doses. Our analysis also shows that the upstream production of IP3 can influence A beta-driven solution patterns in a dose-dependent manner. Model results illustrate and confirm the detrimental impact of iA beta Os on IP3 signaling.

Automated summary

This study developed a mathematical model describing a proposed mechanism by which iA beta Os stimulate PLC to produce IP3, leading to abnormal release of Ca2+. The research found a dose-dependent influence of iA beta Os on IP3-mediated Ca2+ signaling, and also revealed the impact of IP3 production on A beta-driven solution patterns in a dose-dependent manner.