{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:46:30Z","timestamp":1792179990233,"version":"4.4.0"},"reference-count":55,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"29","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,7,17]]},"abstract":"<jats:p>Astrocytes play essential roles in neuropathology. Human astrocytes exhibit unique properties, highlighting the importance of studying astrocytic responses in human models. Varicose projection astrocytes, previously considered exclusive to hominoids and a physiological type of astrocytes, were suggested to reflect pathological burden, albeit direct evidence linking them to neurological diseases has been lacking. Here, we demonstrate that varicose projection astrocytes also appear in other mammals and show, from four distinct human-based disease models, that varicose projection astrocytes are induced by neuroinflammation and characterized by distinctive subcellular features, indicating involvement in cellular stress responses, and their density is increased in aging and human neuropathology. Our findings establish varicose projection astrocytes as a reactive phenotype associated with neuropathology.<\/jats:p>","DOI":"10.1126\/sciadv.ady8204","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:58:48Z","timestamp":1784311128000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["Varicose projection astrocytes: Conserved reactive cells in brain pathology"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-9321","authenticated-orcid":true,"given":"Caterina","family":"Ciani","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."},{"name":"Center for Synaptic Neuroscience and Technology, Italian Institute of Technology, Genoa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Pistorio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4633-7867","authenticated-orcid":true,"given":"Simona","family":"Giancola","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Mearelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2100-5165","authenticated-orcid":true,"given":"Francesca Emma","family":"Mongelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delaram","family":"Forouzeh","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9127-7061","authenticated-orcid":true,"given":"Luana","family":"Campos Soares","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK."},{"name":"BHF Oxford Centre of Research Excellence, University of Oxford, Oxford, UK."},{"name":"Kavli Institute for NanoScience Discovery, University of Oxford, Oxford, UK."},{"name":"British Heart Foundation (BHF)\u2013UK Dementia Research Institute (UK DRI) Centre for Vascular Dementia Research at the University of Oxford, Oxford, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6080-6738","authenticated-orcid":true,"given":"Marta","family":"Gonzalez Martin","sequence":"additional","affiliation":[{"name":"Cajal Institute (CSIC), Madrid, Spain."},{"name":"Cajal Neuroscience Center, CSIC, Campus de Alcal\u00e1 de Henares, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9245-9794","authenticated-orcid":true,"given":"Mandi E.","family":"Lichtenstein","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Mio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3421-8246","authenticated-orcid":true,"given":"Elena","family":"Christou","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Towson University, Towson, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4637-873X","authenticated-orcid":true,"given":"Kyle","family":"Hastings","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Towson University, Towson, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh Quynh","family":"Nguyen Do","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Towson University, Towson, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4825-5769","authenticated-orcid":true,"given":"Paula","family":"Ramos-Gonzalez","sequence":"additional","affiliation":[{"name":"Achucarro Basque Center for Neuroscience, The Basque Biomodels Platforms for Human Research, Leioa, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8672-711X","authenticated-orcid":true,"given":"Carlos","family":"Matute","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of the Basque Country (UPV\/EHU), Leioa, Spain."},{"name":"CIBERNED, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2097-4035","authenticated-orcid":true,"given":"Ugne","family":"Kuliesiute","sequence":"additional","affiliation":[{"name":"Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania."},{"name":"VU LSC-EMBL Partnership Institute for Genome Editing Technologies, Life Sciences Center, Vilnius University, Vilnius, Lithuania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0185-6877","authenticated-orcid":true,"given":"Sari Elena","family":"D\u00f6tterer","sequence":"additional","affiliation":[{"name":"Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8914-117X","authenticated-orcid":true,"given":"Gediminas","family":"Luksys","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Translational Health Research Institute, Vilnius University, Vilnius, Lithuania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9715-641X","authenticated-orcid":true,"given":"Saulius","family":"Rocka","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Translational Health Research Institute, Vilnius University, Vilnius, Lithuania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urte","family":"Neniskyte","sequence":"additional","affiliation":[{"name":"CIBERNED, Madrid, Spain."},{"name":"Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-6655","authenticated-orcid":true,"given":"Daniel C.","family":"Anthony","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1609-5281","authenticated-orcid":true,"given":"Marya","family":"Ayub","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7577-2107","authenticated-orcid":true,"given":"Cinzia","family":"Centelleghe","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-9576","authenticated-orcid":true,"given":"Maria Angeles","family":"Arevalo","sequence":"additional","affiliation":[{"name":"Cajal Institute (CSIC), Madrid, Spain."},{"name":"Cajal Neuroscience Center, CSIC, Campus de Alcal\u00e1 de Henares, Madrid, Spain."},{"name":"CIBERFES, ISCIII, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-8356","authenticated-orcid":true,"given":"Jean-Marie","family":"Gra\u00efc","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0696-7039","authenticated-orcid":true,"given":"Francesco","family":"Petrelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland."},{"name":"School of Pharmacy, University of Rome \u201cTor Vergata\u201d, Rome, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2592-9898","authenticated-orcid":true,"given":"Alexei","family":"Verkhratsky","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2146-9329","authenticated-orcid":true,"given":"Nunzio","family":"Iraci","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2003-522X","authenticated-orcid":true,"given":"Fabio","family":"Cavaliere","sequence":"additional","affiliation":[{"name":"Achucarro Basque Center for Neuroscience, The Basque Biomodels Platforms for Human Research, Leioa, Spain."},{"name":"Department of Neuroscience, University of the Basque Country (UPV\/EHU), Leioa, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2298-7753","authenticated-orcid":true,"given":"Carmen","family":"Mu\u00f1oz-Ballester","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5683-1706","authenticated-orcid":true,"given":"Mootaz M.","family":"Salman","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK."},{"name":"BHF Oxford Centre of Research Excellence, University of Oxford, Oxford, UK."},{"name":"Kavli Institute for NanoScience Discovery, University of Oxford, Oxford, UK."},{"name":"British Heart Foundation (BHF)\u2013UK Dementia Research Institute (UK DRI) Centre for Vascular Dementia Research at the University of Oxford, Oxford, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3725-9713","authenticated-orcid":true,"given":"Francesco P.","family":"Ulloa Severino","sequence":"additional","affiliation":[{"name":"Cajal Institute (CSIC), Madrid, Spain."},{"name":"Cajal Neuroscience Center, CSIC, Campus de Alcal\u00e1 de Henares, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9892-1171","authenticated-orcid":true,"given":"Carmen","family":"Falcone","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Towson University, Towson, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00042.2016"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13123"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-77375-5_3"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01628-9"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-00783-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.03.037"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab311"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.07.004"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-023-01526-9"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP284197"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-00435-y"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-021-00889-6"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11112167"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","unstructured":"A. Verkhratsky A. M. Butt Neuroglia: Function and Pathology (Elsevier 2023).","DOI":"10.1016\/B978-0-12-821565-4.00008-0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.795089"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02565-0"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4707-08.2009"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24605"},{"key":"e_1_3_2_20_2","first-page":"20150428","article-title":"The homeostatic astroglia emerges from evolutionary specialization of neural cells","volume":"371","author":"Verkhratsky A.","year":"2016","unstructured":"A. Verkhratsky, M. Nedergaard, The homeostatic astroglia emerges from evolutionary specialization of neural cells. Philos. Trans. R. Soc. London Ser. B Biol. Sci. 371, 20150428 (2016).","journal-title":"Philos. Trans. R. Soc. London Ser. B Biol. Sci."},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.12.011"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24093"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1477753"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24587"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.05.014"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3906"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.3402\/jev.v3.24641"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04911-1"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12404"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9807456"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12030403"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.07.012"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-53414-9"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23786"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02919-2"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2006.09.007"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01486-5"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.931311"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-64839-7_1"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.340405"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01416"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-01616-5"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9061941"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202201203"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01474541"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.01.010"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2017.23"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2020.10.004"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1136\/svn-2021-001028"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02071-9"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-7-54"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24979"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.075"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155227"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2023.102482"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.902720206"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.ady8204","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T18:00:43Z","timestamp":1784311243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.ady8204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":55,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2026,7,17]]}},"alternative-id":["10.1126\/sciadv.ady8204"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.ady8204","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]},"assertion":[{"value":"2025-05-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eady8204"}}