Neuronal Resilience and Calcium Signaling Pathways in the Context of Synapse Loss and Calcium Leaks: A Computational MODELING Study and Implications for Alzheimer’s Disease

SIAM Journal on Applied Mathematics, Volume 83, Issue 6, Page 2418-2442, December 2023.
Abstract. In this paper, a coupled electro-calcium model was developed and implemented to computationally explore the effects of neuronal synapse loss, in particular in the context of Alzheimer’s disease. Established parameters affected by Alzheimer’s disease, such as synapse loss, calcium leaks at deteriorating synaptic contacts, and downregulation of the calcium buffer calbindin, are subject to this study. Reconstructed neurons are used to define the computational domain for a system of PDEs and ODEs, discretized by finite differences and solved with a semi-implicit second-order time integrator. The results show neuronal resilience during synapse loss. When incorporating calcium leaks at affected synapses, neurons lose their ability to produce synapse-to-nucleus calcium signals, necessary for learning, plasticity, and neuronal survival. Downregulation of calbindin concentrations partially recovers the signaling pathway to the cell nucleus. These results could define future research pathways toward stabilizing the calcium signaling pathways during Alzheimer’s disease. The coupled electro-calcium model was implemented and solved using MATLAB https://github.com/NeuroBox3D/CalcSim.