P073 Simulations using realistic 3D reconstructions of astrocyte endfeet reveal how cell shape alters diffusion in Alzheimer’s disease
Florian Dupeuble*1, Chris Salmon2,5, Hugues Berry1, Keith Murai2, Kaleem Siddiqi3,4,Alexandra L Schober2, J. Benjamin Kacerovsky2,Tabish A. Syed2,5,Rachel Fagen2, Tatiana Tibuleac2Amy Zhou2,Audrey Denizot1
1AIStroSight, INRIA, Université Claude Bernard Lyon 1, Villeurbanne, France
2Research Institute of the McGill University Health Centre, McGill University, Montréal, Canada
3School of Computer Science, McGill University, Montréal, Canada
4MILA - Québec AI Institute, Montreal, Canada
5Centre for Intelligent Machines, School of Computer Science, McGill University, Montreal, Canada
*Email: florian.dupeuble@inria.fr
Introduction
Astrocytes are glial cells involved in numerous brain functions, such as blood flow regulation, toxic waste clearance, or nutrient uptake [1]. They display specialized protrusions, called endfeet, that cover the majority of blood vessels and are suspected to mediate neurovascular coupling.
In Alzheimer’s Disease (AD), astrocytes undergo morphological changes [2]. However, whether endfoot morphology is altered and the functional implications of such ultrastructural changes remain poorly understood to date.
Methods
To study the impact of endfoot shape on astrocyte function, we developed a model of diffusion within high-resolution 3D reconstructions of astrocyte endfeet from WT and AD mice, derived from electron microscopy. 3D manifold tetrahedral endfoot meshes were obtained using Blender and TetWild software. Simulations of calcium diffusion were performed using FEniCS, a finite element methods Python library.
Results
We observe strong differences between the diffusional properties of AD and WT endfeet. While WT endfeet rapidly display a homogeneous calcium concentration, calcium in AD endfeet appears highly compartmentalized. Simulations accounting for the complex ER morphology suggest that they contribute to increased calcium concentration heterogeneity in endfeet, in particular in AD.
Discussion
Our preliminary results suggest that the morphological changes undergone by endfeet in AD impact local diffusion, leading to calcium compartmentalization, which could strongly affect local calcium signaling. Future work will be critical to decipher the functional link between endfoot shape, local calcium signaling, and the neurovascular uncoupling observed in AD [3]. This work provides new insights into the basic mechanisms governing endfoot dysfunction in AD.
Acknowledgements
References
1.https://doi.org/10.1146/annurev-neuro-091922-031205
2.https://doi.org/10.1016/j.coph.2015.09.011
3.https://doi.org/10.1093/brain/awac174
annurev-neuro-091922-031205
