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 (iAβOs), has been linked to the pathogenesis of AD by disrupting cytosolic Ca(2+) 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 AβOs toxicity. We report the development of a mathematical model describing a proposed mechanism by which stimulation of Phospholipase C (PLC) by iAβO, triggers production of IP(3) with consequent abnormal release of Ca(2+) from the endoplasmic reticulum (ER) through activation of IP(3) receptor (IP(3)R) Ca(2+) channels. After validating the model using experimental data, we quantify the effects of intracellular rise in iAβOs on model solutions. Our model validates a dose-dependent influence of iAβOs on IP(3)-mediated Ca(2+) signaling. We investigate Ca(2+) signaling patterns for small and large iAβOs doses and study the role of various parameters on Ca(2+) 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 iAβO alter IP(3)R sensitivity to IP(3) for large doses. Our analysis also shows that the upstream production of IP(3) can influence Aβ-driven solution patterns in a dose-dependent manner. Model results illustrate and confirm the detrimental impact of iAβOs on IP(3) signaling.