Background and Aim: Cognitive decline in the elderlies, Dementia and the most common type of it the
Alzheimer's disease (AD), despite the huge amount of researches, are not yet well understood. The Amyloid beta (AB) hypothesis which is the one taken more seriously, still suffers from ambiguity regarding the cause and effect sequences. Methods In this study, a computational modeling approach is applied to investigate this biophysical role of Aẞ plaques. The model consists of four main parts; neuron, astrocyte, extracellular space, and Aẞ plaque. We used a reference model, a pyramidal neuron in the CAI region of the hippocampus and developed it by the NEURON simulator along with Python. The same procedure has been used for modeling the astrocyte. Then we adopted the newly developed extension of NEURON to model the extracellular dynamic diffusions and reactions. We designated a cubic region that contains the cells and the ions (in this case K+) whose reuptake and diffusion are crucial for maintaining the electrochemical balance. Trying to increase the richness of our compartmental model by adding the system biology concepts into it, we used the repository of biochemical models built by System Biology Markup Language (SBML) to simulate the formation of Aẞ plaque. Aẞ plaque is produced as a result of the accumulation of Aẞ oligomers, which itself is a breakdown of the Amyloid Precursor Protein (APP) belonging to the family of proteins attached to the membrane. We modeled this process of Aẞ plaque formation by SBML tools. Results: In our study, the initial effect of AB plaques, even before causing any biochemical reactions or synaptic changes in the neurons, is their existence in the extracellular space. The steric hindrance resulted from their existence affects the pattern of ionic diffusion and reabsorption. Conclusion: After developing the computational model, we analyzed the pattern of diffusion and reuptake of K+ in the extracellular space in both healthy and pathological conditions, excluding and including the Aẞ plaques respectively. Our simulation results indicate as the K+ flows out of the cell during an action potential, its extracellular concentration and clearance mechanisms, which are regulated by diffusion and the astrocyte, play important roles in keeping the desired level of membrane depolarization and so the excitability of the cell in healthy cases. We examined the healthy pattern of changes in K+ concentration and then, compared it with the case in which Aẞ plaques and their steric hindrance are present in the extracellular space.
