Speaker
Description
Astrocytes are glial cells essential for brain homeostasis, acting as metabolic mediators that couple cerebral blood flow and nutrient uptake to neuronal energy demands. In Alzheimer’s disease (AD), progressive neurodegeneration is accompanied by profound alterations in astrocyte morphology and metabolism. Reactive transformation leads to significant structural remodeling and metabolic changes~\cite{esc}, yet how these morphological alterations contribute to astrocytic metabolic dysfunction remains unclear. Here, we investigate the relationship between AD-related morphological changes and metabolic function using a multiscale mathematical modelling framework ~\cite{far2021, far2023, pap}. The model integrates intracellular energy metabolism with realistic three-dimensional astrocyte morphologies reconstructed from post-mortem human AD and age-matched control. By coupling spatially resolved metabolic pathway dynamics with cellular geometry, we systematically analyse how disease-associated alterations affect energy production, intracellular distribution, and neuronal support capacity. Simulations show that AD-related metabolic dysfunction reduces energetic output and compromises astrocytic support to neurons. Energy deficits arise from the cumulative impairment of multiple pathways rather than a single defect. Notably, morphological remodeling appears to partially compensate for metabolic deficits, suggesting a potential protective response in AD.
Bibliography
@article{esc,
title={Reactive astrocyte nomenclature, definitions, and future directions},
author={Escartin, Carole and Galea, Elena and Lakatos, Andr{\'a}s and O’Callaghan, James P and Petzold, Gabor C and Serrano-Pozo, Alberto and Steinh{\"a}user, Christian and Volterra, Andrea and Carmignoto, Giorgio and Agarwal, Amit and others},
journal={Nature neuroscience},
volume={24},
number={3},
pages={312--325},
year={2021},
publisher={Nature Publishing Group US New York}
}
@article{far2021,
title={A cut finite element method for spatially resolved energy metabolism models in complex neuro-cell morphologies with minimal remeshing},
author={Farina, Sofia and Claus, Susanne and Hale, Jack S and Skupin, Alexander and Bordas, St{\'e}phane PA},
journal={Advanced Modeling and Simulation in Engineering Sciences},
volume={8},
number={1},
pages={5},
year={2021},
publisher={Springer}
}
@article{far2023,
title={Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in Alzheimer’s Disease},
author={Farina, Sofia and Voorsluijs, Val{\'e}rie and Fixemer, Sonja and Bouvier, David S and Claus, Susanne and Ellisman, Mark H and Bordas, St{\'e}phane PA and Skupin, Alexander},
journal={PLoS Computational Biology},
volume={19},
number={9},
pages={e1011464},
year={2023},
publisher={Public Library of Science San Francisco, CA USA}
}
@article{pap,
title={Machine Learning-based Predictions of Spatial Metabolic Profiles Demonstrate the Impact of Morphology on Astrocytic Energy Metabolism},
author={Papavasileiou, Paris and Farina, Sofia and Koronaki, Eleni D and Boudouvis, Andreas G and Bordas, St{\'e}phane PA and Skupin, Alexander},
journal={bioRxiv},
pages={2024--09},
year={2024},
publisher={Cold Spring Harbor Laboratory}
}
