Computational Modeling of NMDAR-Mediated Calcium Dysregulation in Hippocampal Dendritic Spines in Alzheimer's Disease

Disruptions in calcium (Ca²⁺) signaling play a central role in neurodegenerative processes, particularly in Alzheimer's Disease (AD), where Aβ pathology alters synaptic function. This study presents a computational framework integrating an NMDAR model into an existing astrocyte calcium signaling model adapted for hippocampal dendritic spine to examine the effects of Aβ-induced Ca²⁺ dysregulation. The model incorporates NMDAR-mediated Ca²⁺ influx, ER calcium dynamics (IP3Rs, RyRs, SERCA pumps, buffering), to simulate pathological Ca²⁺ signaling. Results indicate that Aβ increases NMDAR burst probability and conductance, leading to sustained cytosolic Ca²⁺ elevation, further influenced by ER-mediated Ca²⁺ release, which contributes to calcium imbalance. Elevated glutamate levels are also observed to exacerbate these effects. The study further examines possible modulatory mechanisms, suggesting that changes in NMDAR kinetics and calcium-buffering capacity may influence intracellular Ca²⁺ stabilization. Findings highlight the complex interplay between glutamate signaling, ER stress, and NMDAR dysfunction in synaptic calcium dysregulation. The model is constrained by physiological values and the range of values for the model outputs are validated where possible with experimental studies. The model provides a framework for investigating potential mechanisms underlying disruptions in calcium homeostasis in AD and could be extended to study CaMKII activation pathways, synaptic remodeling dynamics, and calcium-binding proteins to enhance its predictive capabilities and broader applicability in understanding AD pathology.Clinical Relevance- Aβ-driven calcium dysregulation is implicated in early synaptic dysfunction in AD, making it a potential target for therapeutic strategies. Insights from this model may help in exploring how modulating NMDAR activity, ER calcium regulation, and calcium-buffering proteins could influence synaptic stability offering directions for future research into neuroprotective strategies for AD.