Varicose projection astrocytes: Conserved reactive cells in brain pathology
23 affiliations
- 1Center for Synaptic Neuroscience and Technology, Italian Institute of Technology, Genoa, Italy
- 2Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
- 3BHF Oxford Centre of Research Excellence, University of Oxford, Oxford, UK
- 4British Heart Foundation (BHF)–UK Dementia Research Institute (UK DRI) Centre for Vascular Dementia Research at the University of Oxford, Oxford, UK
- 5Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK
- 6Kavli Institute for NanoScience Discovery, University of Oxford, Oxford, UK
- 7Cajal Institute (CSIC), Madrid, Spain
- 8Cajal Neuroscience Center, CSIC, Campus de Alcalá de Henares, Madrid, Spain
- 9Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA
- 10Department of Biological Sciences, Towson University, Towson, MD, USA
- 11Achucarro Basque Center for Neuroscience, The Basque Biomodels Platforms for Human Research, Leioa, Spain
- 12CIBERNED, Madrid, Spain
- 13Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Spain
- 14Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
- 15VU LSC-EMBL Partnership Institute for Genome Editing Technologies, Life Sciences Center, Vilnius University, Vilnius, Lithuania
- 16Faculty of Medicine, Translational Health Research Institute, Vilnius University, Vilnius, Lithuania
- 17Department of Pharmacology, University of Oxford, Oxford, UK
- 18Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy
- 19CIBERFES, ISCIII, Madrid, Spain
- 20Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
- 21School of Pharmacy, University of Rome “Tor Vergata”, Rome, Italy
- 22Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 23Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
Abstract
Glial cells are fundamental for the pathophysiology of all neurological disorders. Astrocytes, the primary home-ostatic cells of the central nervous system (CNS), exhibit species-specific characteristics, with human astrocytes specifically displaying unique structural and functional features. It is thus essential to investigate human-specific astrocytic responses to neuropathology using human-relevant models. Varicose projection (VP) astrocytes, traditionally considered specific to humans and apes, were suggested to reflect pathological burden, albeit direct evidence linking them to neurological diseases has been lacking. Here, we demonstrate for the first time that VP astrocytes are present in mice and tigers ( Panthera tigris ) and we provide evidence from four distinct human-based models that VP astrocytes are not a distinct physiological astrocyte subtype but rather a novel class of reactive astrocytes associated with neuropathology. Using human induced pluripotent stem cell (hiPSC)-derived astrocytes, mixed neural cultures, and cortical organoids, we showed that VP astrocytes are induced by pro-inflammatory cytokines interleukin-1 β (IL-1 β ) and tumor necrosis factor- α (TNF- α ) or LPS. Notably, cytokine withdrawal reverses the VP phenotype of astrocytes, indicating that it is a transient, inflammation-dependent state. We characterized the distinctive components of varicosities, including markers for extracellular vesicles, mitochondria, Golgi and endoplasmic reticulum components, suggesting roles in cellular stress responses and metabolic dysregulation. We further validated the pathological relevance of VP astrocytes by documenting their significant enrichment in postmortem brain samples from patients with several neurodegenerative diseases including as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, as well as in surgical resections from patients with epilepsy due to hippocampal sclerosis or brain tumors, including previously unreported subcortical regions such as basal ganglia. Additionally, we identified a higher number of VP astrocytes also in mouse astrocytes upon treatment with pro-inflammatory cytokines, suggesting that formation of VP astrocytes is an evolutionarily conserved astrocytic response to neuroinflammation. Our findings point to VP astrocytes as a novel reactive astrocyte subtype closely linked to neuropathology, highlighting their potential as biomarkers and therapeutic targets in neurological diseases. This study lays the groundwork for future investigations into the mechanisms driving VP astrocyte formation and their broader implications in neuropathology.
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BibTeX
@article{ciani2026varicose,
title = {{Varicose projection astrocytes: Conserved reactive cells in brain pathology}},
author = {Caterina Ciani and Giulio Pistorio and Simona Giancola and Marika Mearelli and Francesca Emma Mongelli and Delaram Forouzeh and Luana Campos Soares and Marta González Martín and Mandi E. Lichtenstein and Luca Mio and Elena Christou and Kyle Hastings and Anh Quynh Nguyen Do and Paula Ramos‐Gonzalez and Carlos Matute and Ugnė Kuliešiūtė and Sari Elena Dötterer and Gediminas Lukšys and Saulius Ročka and Urtė Neniškytė and Daniel C. Anthony and Marya Ayub and Cinzia Centelleghe and María‐Ángeles Arévalo and Jean‐Marie Graïc and Francesco Petrelli and Alexei Verkhratsky and Nunzio Iraci and Fabio Cavaliere and Carmen Muñoz‐Ballester and Mootaz M. Salman and Francesco Paolo Ulloa Severino and Carmen Falcone},
journal = {Science Advances},
year = {2026},
month = jul,
doi = {10.1126/sciadv.ady8204},
url = {https://doi.org/10.1126/sciadv.ady8204},
note = {CC BY},
}
RIS
TY - JOUR
TI - Varicose projection astrocytes: Conserved reactive cells in brain pathology
AU - Caterina Ciani
AU - Giulio Pistorio
AU - Simona Giancola
AU - Marika Mearelli
AU - Francesca Emma Mongelli
AU - Delaram Forouzeh
AU - Luana Campos Soares
AU - Marta González Martín
AU - Mandi E. Lichtenstein
AU - Luca Mio
AU - Elena Christou
AU - Kyle Hastings
AU - Anh Quynh Nguyen Do
AU - Paula Ramos‐Gonzalez
AU - Carlos Matute
AU - Ugnė Kuliešiūtė
AU - Sari Elena Dötterer
AU - Gediminas Lukšys
AU - Saulius Ročka
AU - Urtė Neniškytė
AU - Daniel C. Anthony
AU - Marya Ayub
AU - Cinzia Centelleghe
AU - María‐Ángeles Arévalo
AU - Jean‐Marie Graïc
AU - Francesco Petrelli
AU - Alexei Verkhratsky
AU - Nunzio Iraci
AU - Fabio Cavaliere
AU - Carmen Muñoz‐Ballester
AU - Mootaz M. Salman
AU - Francesco Paolo Ulloa Severino
AU - Carmen Falcone
PY - 2026
DA - 2026/07/17
JO - Science Advances
DO - 10.1126/sciadv.ady8204
UR - https://doi.org/10.1126/sciadv.ady8204
AB - Glial cells are fundamental for the pathophysiology of all neurological disorders. Astrocytes, the primary home-ostatic cells of the central nervous system (CNS), exhibit species-specific characteristics, with human astrocytes specifically displaying unique structural and functional features. It is thus essential to investigate human-specific astrocytic responses to neuropathology using human-relevant models. Varicose projection (VP) astrocytes, traditionally considered specific to humans and apes, were suggested to reflect pathological burden, albeit direct evidence linking them to neurological diseases has been lacking. Here, we demonstrate for the first time that VP astrocytes are present in mice and tigers ( Panthera tigris ) and we provide evidence from four distinct human-based models that VP astrocytes are not a distinct physiological astrocyte subtype but rather a novel class of reactive astrocytes associated with neuropathology. Using human induced pluripotent stem cell (hiPSC)-derived astrocytes, mixed neural cultures, and cortical organoids, we showed that VP astrocytes are induced by pro-inflammatory cytokines interleukin-1 β (IL-1 β ) and tumor necrosis factor- α (TNF- α ) or LPS. Notably, cytokine withdrawal reverses the VP phenotype of astrocytes, indicating that it is a transient, inflammation-dependent state. We characterized the distinctive components of varicosities, including markers for extracellular vesicles, mitochondria, Golgi and endoplasmic reticulum components, suggesting roles in cellular stress responses and metabolic dysregulation. We further validated the pathological relevance of VP astrocytes by documenting their significant enrichment in postmortem brain samples from patients with several neurodegenerative diseases including as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, as well as in surgical resections from patients with epilepsy due to hippocampal sclerosis or brain tumors, including previously unreported subcortical regions such as basal ganglia. Additionally, we identified a higher number of VP astrocytes also in mouse astrocytes upon treatment with pro-inflammatory cytokines, suggesting that formation of VP astrocytes is an evolutionarily conserved astrocytic response to neuroinflammation. Our findings point to VP astrocytes as a novel reactive astrocyte subtype closely linked to neuropathology, highlighting their potential as biomarkers and therapeutic targets in neurological diseases. This study lays the groundwork for future investigations into the mechanisms driving VP astrocyte formation and their broader implications in neuropathology.
SN - 2375-2548
ER -