Computational Modeling for the Dysregulation of Calcium in Alzheimer Disease

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder. According to Alzheimer Disease International (ADI), people develop dementia every 3 seconds in the world. ßA (Beta- Amyloid) is the main constituent of neuritic plaques. Amyloid beta (Aβ) accumulations at the intracellular level can increase the release of Ca2+ from the internal store endoplasmic reticulum (ER). Calcium is a very important signaling molecule where Ca2+ ion plays an important role in neuronal signaling. Abnormalities in calcium regulation have been reported in several neurodegenerative diseases. Increased oscillations of Ca2+ ion concentration is due to the most important cellular component known as IP3R. In this study 3-state model was used to describe all observed gating behavious in IP3R channels in Sf9 cells. Here, a simulated algorithm was adopted to optimize the parameters in a modified model by fitting the experimental results of open probabilities (Po) of IP3RPS1M146L saturates at significantly lower IP3 concentrations and its peak value is higher as compared to the IP3RPS1WT. By modifying a minimum number of model parameters, the 3-state model was applied to fit observed gating behaviors in channel Po. This research applied, IP3R stochastic model which was used to investigate the Ca2+ level puffs (amplitudes and duration) in normal cells and the one with AD cells. Investigating the model solution can provide important information on the impact of Aβ on Ca2+ basal levels at various timescales. Although it is unclear how Aβ disrupts the intracellular Ca2+ homeostasis there is an evidence that Aβ directly affects the production of IP3, through Ryanodine receptor (RyR) and plasma membrane by calcium-induced calcium release (CICR). We will use the results of these findings and validate them by computational modeling. Our future planning is to build a whole-cell model and check its effects on the elementary Ca2+ release events such as Puffs at the local and global levels.