{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:48:26Z","timestamp":1787500106364,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01cwqze88","award":["R01AG071996"],"award-info":[{"award-number":["R01AG071996"]}]},{"name":"National Institutes of Health\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01cwqze88","award":["R01AG087406"],"award-info":[{"award-number":["R01AG087406"]}]},{"name":"National Institutes of Health\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01cwqze88","award":["RF1AG078684"],"award-info":[{"award-number":["RF1AG078684"]}]},{"name":"National Institutes of Health\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01cwqze88","award":["R01AG086344"],"award-info":[{"award-number":["R01AG086344"]}]},{"name":"National Institutes of Health\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01cwqze88","award":["T32AI055432"],"award-info":[{"award-number":["T32AI055432"]}]},{"name":"National Institutes of Health\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01cwqze88","award":["F31NS135897"],"award-info":[{"award-number":["F31NS135897"]}]},{"name":"Owen\u2019s Family Foundation"},{"name":"Cure Alzheimer\u2019s Fund\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/05ewr7t48"},{"name":"Harrison Family Foundation"},{"name":"Steven A. Newman AD Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Genotoxic stress, which includes DNA damage and the mis-localization of DNA and RNA, is a defining feature of tauopathies, Alzheimer\u2019s disease, and several other neurodegenerative disorders. Recent findings indicate that activation of the innate immune system in response to genotoxic stress can drive harmful neuroinflammation, compromise neuronal integrity, and promote neurodegeneration. Multiple innate immune sensors of genotoxic stress have recently been discovered, but the contributions of many of these emerging nucleic acid\u2013sensing pathways in neurodegenerative disease pathogenesis remain largely unexplored. Z-DNA binding protein 1 (ZBP1) is one such recently discovered genotoxic stress sensor that has been shown to incite various forms of cell death as well as proinflammatory cytokine production in response to left-handed Z conformations of DNA (Z-DNA) and RNA (Z-RNA). Here, we show that ZBP1 deletion provides protection against tau pathology and neuronal loss in the PS19 mouse model of tauopathy. Moreover, we find that this rescue of tauopathy seen with ZBP1 ablation is associated with dampened activation of microglia and astrocytes. These findings identify ZBP1 as a pivotal genotoxic stress sensor that drives tau pathology, gliosis, and neuronal loss in tauopathy. This work further suggests that targeting ZBP1 may offer a therapeutic strategy to treat tau-mediated neurodegenerative disease.<\/jats:p>","DOI":"10.3390\/cells15070591","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:48:41Z","timestamp":1774532921000},"page":"591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Genotoxic Stress Sensor ZBP1 Drives Tau Pathology"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7984-5361","authenticated-orcid":false,"given":"Jessica M.","family":"Thanos","sequence":"first","affiliation":[{"name":"Center for Brain Immunology and Glia (BIG), Harrison Family Translational Research Center in Alzheimer\u2019s and Neurodegenerative Diseases, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia C.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Center for Brain Immunology and Glia (BIG), Harrison Family Translational Research Center in Alzheimer\u2019s and Neurodegenerative Diseases, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5677-0977","authenticated-orcid":false,"given":"Nick R.","family":"Natale","sequence":"additional","affiliation":[{"name":"Center for Brain Immunology and Glia (BIG), Harrison Family Translational Research Center in Alzheimer\u2019s and Neurodegenerative Diseases, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Global Biothreats Graduate Training Program, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2801-2746","authenticated-orcid":false,"given":"Ana","family":"Royo Marco","sequence":"additional","affiliation":[{"name":"Center for Brain Immunology and Glia (BIG), Harrison Family Translational Research Center in Alzheimer\u2019s and Neurodegenerative Diseases, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Puchalski","sequence":"additional","affiliation":[{"name":"Center for Brain Immunology and Glia (BIG), Harrison Family Translational Research Center in Alzheimer\u2019s and Neurodegenerative Diseases, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6795-0866","authenticated-orcid":false,"given":"John R.","family":"Lukens","sequence":"additional","affiliation":[{"name":"Center for Brain Immunology and Glia (BIG), Harrison Family Translational Research Center in Alzheimer\u2019s and Neurodegenerative Diseases, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Global Biothreats Graduate Training Program, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1038\/s41467-022-29552-6","article-title":"Microglial NF-\u03baB drives tau spreading and toxicity in a mouse model of tauopathy","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/s41593-023-01315-6","article-title":"Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience","volume":"26","author":"Udeochu","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41586-019-1769-z","article-title":"NLRP3 inflammasome activation drives tau pathology","volume":"575","author":"Ising","year":"2019","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1742-2094-7-56","article-title":"LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice","volume":"7","author":"Lee","year":"2010","journal-title":"J. Neuroinflamm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.neuron.2010.08.023","article-title":"Regulation of tau pathology by the microglial fractalkine receptor","volume":"68","author":"Bhaskar","year":"2010","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"116232","DOI":"10.1016\/j.celrep.2025.116232","article-title":"Emerging roles for innate and adaptive immunity in tauopathies","volume":"44","author":"Johnson","year":"2025","journal-title":"Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s44318-024-00352-6","article-title":"RNA dysregulation in neurodegenerative diseases","volume":"44","author":"Li","year":"2025","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.dnarep.2008.03.012","article-title":"Mitochondrial DNA damage and repair in neurodegenerative disorders","volume":"7","author":"Yang","year":"2008","journal-title":"DNA Repair"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2014.06.034","article-title":"DNA damage and its links to neurodegeneration","volume":"83","author":"Madabhushi","year":"2014","journal-title":"Neuron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e70305","DOI":"10.1002\/alz.70305","article-title":"STING deletion protects against amyloid beta-induced Alzheimer\u2019s disease pathogenesis","volume":"21","author":"Thanos","year":"2025","journal-title":"Alzheimers Dement"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/s43587-022-00337-2","article-title":"Activation of innate immune cGAS-STING pathway contributes to Alzheimer\u2019s pathogenesis in 5xFAD mice","volume":"3","author":"Xie","year":"2023","journal-title":"Nat. Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1038\/s12276-024-01295-y","article-title":"Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer\u2019s disease pathologies","volume":"56","author":"Chung","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.immuni.2020.03.017","article-title":"Distinct and Orchestrated Functions of RNA Sensors in Innate Immunity","volume":"53","author":"Liu","year":"2020","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1038\/s41590-024-01966-y","article-title":"DNA-sensing pathways in health, autoinflammatory and autoimmune diseases","volume":"25","author":"Dong","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.it.2017.11.002","article-title":"ZBP1: Innate Sensor Regulating Cell Death and Inflammation","volume":"39","author":"Kuriakose","year":"2018","journal-title":"Trends. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e20221156","DOI":"10.1084\/jem.20221156","article-title":"The Z-nucleic acid sensor ZBP1 in health and disease","volume":"220","author":"Maelfait","year":"2023","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s42003-018-0237-x","article-title":"Z-DNA and Z-RNA in human disease","volume":"2","author":"Herbert","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.cell.2020.02.050","article-title":"Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis","volume":"180","author":"Zhang","year":"2020","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"aag2045","DOI":"10.1126\/sciimmunol.aag2045","article-title":"ZBP1\/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways","volume":"1","author":"Kuriakose","year":"2016","journal-title":"Sci. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e55839","DOI":"10.15252\/embr.202255839","article-title":"Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1","volume":"23","author":"Peng","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/s41586-025-09705-5","article-title":"Host cell Z-RNAs activate ZBP1 during virus infections","volume":"648","author":"Yin","year":"2025","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.immuni.2018.11.017","article-title":"The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons","volume":"50","author":"Daniels","year":"2019","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2525296122","DOI":"10.1073\/pnas.2525296122","article-title":"Identification of an IRF-ZBP1-caspase-8-NINJ1 axis in driving PANoptosis and pathology during alcohol-associated liver disease","volume":"122","author":"Qin","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1038\/s41586-022-04974-w","article-title":"ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation","volume":"607","author":"Verdonck","year":"2022","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/s41586-022-04878-9","article-title":"ADAR1 averts fatal type I interferon induction by ZBP1","volume":"607","author":"Jiao","year":"2022","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109858","DOI":"10.1016\/j.celrep.2021.109858","article-title":"ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis","volume":"37","author":"Karki","year":"2021","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s41586-022-04896-7","article-title":"ADAR1 mutation causes ZBP1-dependent immunopathology","volume":"607","author":"Hubbard","year":"2022","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e20191913","DOI":"10.1084\/jem.20191913","article-title":"Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation","volume":"217","author":"Devos","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109938","DOI":"10.1016\/j.clim.2024.109938","article-title":"Z-nucleic acid sensor ZBP1 in sterile inflammation","volume":"261","author":"Song","year":"2024","journal-title":"Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e2514837122","DOI":"10.1073\/pnas.2514837122","article-title":"Stress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging","volume":"122","author":"Lei","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1016\/j.immuni.2025.07.024","article-title":"Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer\u2019s disease","volume":"58","author":"Song","year":"2025","journal-title":"Immunity"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.brainresrev.2008.01.001","article-title":"Role of DNA dynamics in Alzheimer\u2019s disease","volume":"58","author":"Vasudevaraju","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1385\/NMM:2:3:289","article-title":"First evidence to show the topological change of DNA from B-dNA to Z-DNA conformation in the hippocampus of Alzheimer\u2019s brain","volume":"2","author":"Suram","year":"2002","journal-title":"Neuromol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1007\/s11010-023-04702-6","article-title":"ZBP1 mediates the progression of Alzheimer\u2019s disease via pyroptosis by regulating IRF3","volume":"478","author":"Guo","year":"2023","journal-title":"Mol. Cell Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.neuron.2007.01.010","article-title":"Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model","volume":"53","author":"Yoshiyama","year":"2007","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/(SICI)1097-4547(19970415)48:2<128::AID-JNR5>3.0.CO;2-E","article-title":"Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau","volume":"48","author":"Jicha","year":"1997","journal-title":"J. Neurosci. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2250266","DOI":"10.1002\/eji.202250266","article-title":"The innate immune response in tauopathies","volume":"53","author":"Johnson","year":"2023","journal-title":"Eur. J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/s41586-023-05788-0","article-title":"Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy","volume":"615","author":"Chen","year":"2023","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/nn.4132","article-title":"Depletion of microglia and inhibition of exosome synthesis halt tau propagation","volume":"18","author":"Asai","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1093\/brain\/awv081","article-title":"Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain","volume":"138","author":"Maphis","year":"2015","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s00401-025-02879-2","article-title":"Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons","volume":"149","author":"Broekaart","year":"2025","journal-title":"Acta Neuropathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.neuron.2023.10.014","article-title":"STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges","volume":"112","author":"Yang","year":"2024","journal-title":"Neuron"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e2118819119","DOI":"10.1073\/pnas.2118819119","article-title":"STING mediates neurodegeneration and neuroinflammation in nigrostriatal alpha-synucleinopathy","volume":"119","author":"Hinkle","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106065","DOI":"10.1016\/j.bbi.2025.106065","article-title":"Crosstalk between DNA damage and cGAS-STING immune pathway drives neuroinflammation and dopaminergic neurodegeneration in Parkinson\u2019s disease","volume":"130","author":"Khan","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.cell.2020.09.020","article-title":"TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS\/STING in ALS","volume":"183","author":"Yu","year":"2020","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s00401-024-02688-z","article-title":"Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia","volume":"147","author":"Marques","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1038\/s41467-021-23004-3","article-title":"ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer","volume":"12","author":"Baik","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"116384","DOI":"10.1016\/j.celrep.2025.116384","article-title":"Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer","volume":"44","author":"Jiang","year":"2025","journal-title":"Cell Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"eabf6290","DOI":"10.1126\/sciadv.abf6290","article-title":"ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation","volume":"7","author":"Yang","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"116314","DOI":"10.1016\/j.celrep.2025.116314","article-title":"ZBP1 pathway promotes tumor immunogenicity in the combination of anti-HER2 therapy and epigenetic therapy","volume":"44","author":"Wang","year":"2025","journal-title":"Cell Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/7\/591\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T14:04:15Z","timestamp":1774533855000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/7\/591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,26]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cells15070591"],"URL":"https:\/\/doi.org\/10.3390\/cells15070591","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,26]]}}}