Speaker
Description
Astrocytes play an important role in the regulation and support of neural functions in the central nervous system. Neurodegenerative diseases (ND), have been linked to the development of pathological astrocytic phenotypes that result in changes in cellular morphology and mitochondrial dysfunction \cite{r2021, s2024}. Calcium (Ca2+) dysregulation influence key metabolic pathways that can lead to ND \cite{v2024}. While recent studies indicate that neuronal loss is triggered by impaired energy metabolism of astrocytes, the underlying mechanisms are still not fully understood.
To address this gap, we have developed a mechanistic multi-scale model that describes the dynamical crosstalk between Ca2+ signaling and mitochondrial activity in pathological morphological of astrocytes in ND condition. Spatially resolved astrocyte metabolism is described by a reaction-diffusion system and solved by Finite Element Methods. Our results show a difference in metabolic energy profiles between morphologies of healthy and diseases astrocytes. Healthy cells produce enough ATP to sustain long diffusion of metabolites and variation in lactate concentration may potentially influence the Astrocyte-Neuron Lactate Shuttle. Numerical solutions also corroborated previous studies were variations in chemical reaction distribution in the cell can influence the overall metabolite concentration \cite{f2023}. This demonstrates how mechanistic modelling can reveal underlying metabolic mechanisms of ND.
Bibliography
@article{r2021,
title = {Astrocytic atrophy as a pathological feature of {Parkinson}’s disease with {LRRK2} mutation},
volume = {7},
issn = {2373-8057},
url = {https://www.nature.com/articles/s41531-021-00175-w},
doi = {10.1038/s41531-021-00175-w},
abstract = {Abstract
The principal hallmark of Parkinson’s disease (PD) is the selective neurodegeneration of dopaminergic neurones. Mounting evidence suggests that astrocytes may contribute to dopaminergic neurodegeneration through decreased homoeostatic support and deficient neuroprotection. In this study, we generated induced pluripotent stem cells (iPSC)-derived astrocytes from PD patients with LRRK2
(G2019S)
mutation and healthy donors of the similar age. In cell lines derived from PD patients, astrocytes were characterised by a significant decrease in S100B and GFAP-positive astrocytic profiles associated with marked decrease in astrocyte complexity. In addition, PD-derived astrocytes demonstrated aberrant mitochondrial morphology, decreased mitochondrial activity and ATP production along with an increase of glycolysis and increased production of reactive oxygen species. Taken together, our data indicate that astrocytic asthenia observed in patient-derived cultures with LRRK2
(G2019S)
mutation may contribute to neuronal death through decreased homoeostatic support, elevated oxidative stress and failed neuroprotection.},
language = {en},
number = {1},
urldate = {2026-03-13},
journal = {npj Parkinson's Disease},
author = {Ramos-Gonzalez, Paula and Mato, Susana and Chara, Juan Carlos and Verkhratsky, Alexei and Matute, Carlos and Cavaliere, Fabio},
month = mar,
year = {2021},
pages = {31},
}
@misc{s2024,
title = {Astrocyte-derived {MFG}-{E8} facilitates microglial synapse elimination in {Alzheimer}’s disease mouse models},
copyright = {http://creativecommons.org/licenses/by-nc-nd/4.0/},
url = {http://biorxiv.org/lookup/doi/10.1101/2024.08.31.606944},
doi = {10.1101/2024.08.31.606944},
abstract = {Summary
Region-specific synapse loss is an early pathological hallmark in Alzheimer’s disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are ‘bulbous’ in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated
in vitro
and
in vivo
approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down
Mfge8
specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.},
language = {en},
urldate = {2026-03-13},
author = {Sokolova, Dimitra and Addington Ghansah, Shari and Puletti, Francesca and Georgiades, Tatiana and De Schepper, Sebastiaan and Zheng, Yongjing and Crowley, Gerard and Wu, Ling and Rueda-Carrasco, Javier and Koutsiouroumpa, Angeliki and Muckett, Philip and Freeman, Oliver J. and Khakh, Baljit S. and Hong, Soyon},
month = sep,
year = {2024},
}
@article{v2024,
title = {Calcium oscillations optimize the energetic efficiency of mitochondrial metabolism},
volume = {27},
issn = {25890042},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2589004224002992},
doi = {10.1016/j.isci.2024.109078},
language = {en},
number = {3},
urldate = {2026-03-13},
journal = {iScience},
author = {Voorsluijs, Valérie and Avanzini, Francesco and Falasco, Gianmaria and Esposito, Massimiliano and Skupin, Alexander},
month = mar,
year = {2024},
pages = {109078},
}
@article{f2023,
title = {Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in {Alzheimer}’s {Disease}},
volume = {19},
issn = {1553-7358},
url = {https://dx.plos.org/10.1371/journal.pcbi.1011464},
doi = {10.1371/journal.pcbi.1011464},
abstract = {Astrocytes with their specialised morphology are essential for brain homeostasis as metabolic mediators between blood vessels and neurons. In neurodegenerative diseases such as Alzheimer’s disease (AD), astrocytes adopt reactive profiles with molecular and morphological changes that could lead to the impairment of their metabolic support and impact disease progression. However, the underlying mechanisms of how the metabolic function of human astrocytes is impaired by their morphological changes in AD are still elusive. To address this challenge, we developed and applied a metabolic multiscale modelling approach integrating the dynamics of metabolic energy pathways and physiological astrocyte morphologies acquired in human AD and age-matched control brain samples. The results demonstrate that the complex cell shape and intracellular organisation of energetic pathways determine the metabolic profile and support capacity of astrocytes in health and AD conditions. Thus, our mechanistic approach indicates the importance of spatial orchestration in metabolism and allows for the identification of protective mechanisms against disease-associated metabolic impairments.},
language = {en},
number = {9},
urldate = {2026-03-13},
journal = {PLOS Computational Biology},
author = {Farina, Sofia and Voorsluijs, Valérie and Fixemer, Sonja and Bouvier, David S. and Claus, Susanne and Ellisman, Mark H. and Bordas, Stéphane P. A. and Skupin, Alexander},
editor = {Berry, Hugues},
month = sep,
year = {2023},
pages = {e1011464},
}
