Network-Based Analysis of Human Astrocytes Links Aging to Neurodegenerative and Cardiovascular Diseases

Bota, P. M.; Picon-Pages, P.; Fanlo-Ucar, H.; Almabhouh, S.; Bagudanch, O.; Zeylan, M. E.; Senyuz, S.; Gohl, P.; Molina-Fernandez, R.; Fernandez-Fuentes, N.; Barbu, E.; Vicente, R.; Nattel, S.; Ois, A.; Puig-Pijoan, A.; Garcia-Ojalvo, J.; Keskin, O.; Gursoy, A.; Munoz, F. J.; Oliva, B.

doi:10.1101/2025.11.05.686746

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bioRxiv · 10.1101/2025.11.05.686746

Network-Based Analysis of Human Astrocytes Links Aging to Neurodegenerative and Cardiovascular Diseases

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Abstract

Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms of astrocytic aging remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 {micro}M H2O2), we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defences, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signalling. We then performed seven network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte H2O2-responsive genes and six with phenotype-associated gene sets (Alzheimers disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5% scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, -actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between APP-VCP/p97 and p53-14-3-3{zeta} that link proteostasis and stress signalling. Together, these findings define a conserved astrocytic vulnerability network that may couple neurodegeneration with cardiovascular disease and nominate structurally testable targets for biomarkers and interventions.

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Bota, P. M., Picon-Pages, P., Fanlo-Ucar, H., Almabhouh, S., Bagudanch, O., Zeylan, M. E., Senyuz, S., Gohl, P., Molina-Fernandez, R., Fernandez-Fuentes, N., Barbu, E., Vicente, R., Nattel, S., Ois, A., Puig-Pijoan, A., Garcia-Ojalvo, J., Keskin, O., Gursoy, A., Munoz, F. J., Oliva, B.. 2025-11-06. Network-Based Analysis of Human Astrocytes Links Aging to Neurodegenerative and Cardiovascular Diseases. https://doi.org/10.1101/2025.11.05.686746

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