{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:21:07Z","timestamp":1793744467270,"version":"4.6.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer\u2019s disease (AD), alongside \u00df-amyloid deposition and the formation of neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part of the innate immune system, has been implicated in the neuropathology of both preclinical amyloid and tau transgenic models. Activation of the NLRP3 pathway involves an initial priming step, which increases the expression of Nlrp3 and interleukin (IL)-1\u03b2, followed by the assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC, and caspase-1. This assembly leads to the proteolytic maturation of the pro-inflammatory cytokines IL-1\u03b2 and IL-18. Additionally, the NLRP3 inflammasome induces Gasdermin D (GSDMD) cleavage, forming membrane pores through which IL-1\u03b2 and IL-18 are secreted. Inhibition of NLRP3 has been shown to enhance plaque clearance by modulating microglial activation. Furthermore, blocking NLRP3 in tau transgenic mice has been found to reduce tau phosphorylation by affecting the activity of certain tau kinases and phosphatases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, organotypic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1\u03b2 secretion levels in the presence and absence of NLRP3 inhibitors. The role of NLRP3 activity was investigated in full-body\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      knockout mice crossbred with the tau transgenic P301S model. Additionally, full-body and microglia-selective\n                      <jats:italic>Gsdmd<\/jats:italic>\n                      knockout mice were crossbred with P301S mice, and tau pathology and neurodegeneration were evaluated at early and late stages of the disease using immunohistochemistry and biochemical assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Activation of the NLRP3 pathway was observed in the mouse organotypic slice culture (OSC) model following stimulation with LPS and nigericin or exposure to tau seeds. However,\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      deficiency did not mitigate tauopathy or neurodegeneration in P301S mice\n                      <jats:italic>in vivo<\/jats:italic>\n                      , showing only a minor effect on plasma neurofilament (NF-L) levels. Consistently,\n                      <jats:italic>Gsdmd<\/jats:italic>\n                      deficiency did not alter tau pathology in P301S mice. Furthermore, neither full-body nor microglia-selective\n                      <jats:italic>Gsdmd<\/jats:italic>\n                      deletion had an impact on neuronal pathology or the release of pro-inflammatory cytokines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The absence of key components of the NLRP3 inflammasome pathway did not yield a beneficial effect on tau pathology or neurodegeneration in the preclinical Tau-P301S mouse model of AD. Nonetheless, organotypic slice cultures could serve as a valuable\n                      <jats:italic>ex vivo<\/jats:italic>\n                      mechanistic model for evaluating NLRP3 pathway activation and pharmacological inhibitors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2024.1459134","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:44:16Z","timestamp":1727138656000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["NLRP3 inflammasome activation and pyroptosis are dispensable for tau pathology"],"prefix":"10.3389","volume":"16","author":[{"given":"Ine","family":"Paesmans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristof","family":"Van Kolen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Vandermeeren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yu","family":"Shih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Wuyts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleur","family":"Boone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Garcia Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolien","family":"Grauwen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Van Hauwermeiren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Van Opdenbosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Lamkanfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"van Loo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Bottelbergs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"9340","DOI":"10.1523\/JNEUROSCI.22-21-09340.2002","article-title":"Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein","volume":"22","author":"Allen","year":"2002","journal-title":"J. Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/S0197-4580(00)00094-4","article-title":"Microglia, amyloid and dementia in Alzheimer disease","volume":"21","author":"Arends","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.neuron.2016.05.018","article-title":"Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases","volume":"91","author":"Bacioglu","year":"2016","journal-title":"Neuron"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2665","DOI":"10.1523\/JNEUROSCI.23-07-02665.2003","article-title":"A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation","volume":"23","author":"Bamberger","year":"2003","journal-title":"J. Neurosci."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/glia.440020605","article-title":"Patterns of gliosis in alzheimer\u2019s disease and aging cerebrum","volume":"2","author":"Beach","year":"1989","journal-title":"Glia"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.1016\/j.neurobiolaging.2013.12.010","article-title":"Missense variant in TREML2 protects against Alzheimer\u2019s disease","volume":"35","author":"Benitez","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/S0140-6736(01)05625-2","article-title":"In-vivo measurement of activated microglia in dementia","volume":"358","author":"Cagnin","year":"2001","journal-title":"Lancet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1038\/nn.3531","article-title":"A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation","volume":"16","author":"Goldmann","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa1211851","article-title":"TREM2 variants in Alzheimer\u2019s disease","volume":"368","author":"Guerreiro","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1038\/NI.1636","article-title":"The NALP3 inflammasome is involved in the innate immune response to amyloid-\u03b2","volume":"9","author":"Halle","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease HHS public access","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nri3705","article-title":"Innate immune activation in neurodegenerative disease","volume":"14","author":"Heneka","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nature11729","article-title":"NLRP3 is activated in Alzheimer\u2019s disease and contributes to pathology in APP\/PS1 mice","volume":"493","author":"Heneka","year":"2012","journal-title":"Nature"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/nrn3880","article-title":"Immune attack: the role of inflammation in Alzheimer disease","volume":"16","author":"Heppner","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1038\/S41593-018-0242-X","article-title":"Microglia in neurodegeneration","volume":"21","author":"Hickman","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/ng.803","article-title":"Common variants at ABCA7, MS4A6A\/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer\u2019s disease","volume":"43","author":"Hollingworth","year":"2011","journal-title":"Nat. Genet."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/imm.13221","article-title":"Hallmarks of NLRP3 inflammasome activation are observed in organotypic hippocampal slice culture","volume":"161","author":"Hoyle","year":"2020","journal-title":"Immunology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-2094-2-25","article-title":"A refined in vitro model to study inflammatory responses in organotypic membrane culture of postnatal rat hippocampal slices","volume":"2","author":"Huuskonen","year":"2005","journal-title":"J. Neuroinflammation"},{"key":"ref23","doi-asserted-by":"publisher","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":"ref24","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1056\/NEJMoa1211103","article-title":"Variant of TREM2 associated with the risk of Alzheimer\u2019s disease","volume":"368","author":"Jonsson","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.4049\/jimmunol.1101121","article-title":"TLR2 is a primary receptor for Alzheimer\u2019s amyloid peptide to trigger neuroinflammatory activation","volume":"188","author":"Liu","year":"2012","journal-title":"J. Immunol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1111\/j.1600-065X.2011.01044.x","article-title":"Caspase-1-induced pyroptotic cell death","volume":"243","author":"Miao","year":"2011","journal-title":"Immunol. 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Dis."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1002\/brb3.2063","article-title":"Pyroptosis executive protein GSDMD as a biomarker for diagnosis and identification of Alzheimer\u2019s disease","volume":"11","author":"Shen","year":"2021","journal-title":"Brain Behav."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1323409","DOI":"10.3389\/fimmu.2024.1323409","article-title":"Inflammasome signaling is dispensable for \u00df-amyloid-induced neuropathology in preclinical models of Alzheimer\u2019s disease","volume":"15","author":"Srinivasan","year":"2024","journal-title":"Front. Immunol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1007\/s00401-018-01957-y","article-title":"Aggregated tau activates NLRP3\u2013ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded tau pathology in vivo","volume":"137","author":"Stancu","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/ni.1836","article-title":"CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer","volume":"11","author":"Stewart","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"R568","DOI":"10.1016\/j.cub.2016.02.019","article-title":"Pyroptosis","volume":"11","author":"Vande Walle","year":"2016","journal-title":"Current Biol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3233\/JAD-180404","article-title":"Anti-tau monoclonal antibodies derived from soluble and filamentous tau show diverse functional properties in vitro and in vivo","volume":"65","author":"Vandermeeren","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/nature25158","article-title":"Microglia-derived ASC specks crossseed amyloid-\u03b2 in Alzheimer\u2019s disease","volume":"552","author":"Venegas","year":"2017","journal-title":"Nature"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"e10248","DOI":"10.15252\/emmm.201810248","article-title":"Inflammasomes in neuroinflammatory and neurodegenerative diseases","volume":"11","author":"Voet","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"2663","DOI":"10.1016\/j.apsb.2023.04.008","article-title":"GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson\u2019s disease","volume":"13","author":"Wang","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1038\/s41588-021-00921-z","article-title":"A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer\u2019s disease","volume":"53","author":"Wightman","year":"2021","journal-title":"Nat. Genet."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1007\/s12035-017-0467-9","article-title":"NLRP3 inflammasome inhibitor ameliorates amyloid pathology in a mouse model of Alzheimer\u2019s disease","volume":"55","author":"Yin","year":"2017","journal-title":"Mol. Neurobiol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1459134\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:44:18Z","timestamp":1727138658000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1459134\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,24]]},"references-count":37,"alternative-id":["10.3389\/fnagi.2024.1459134"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2024.1459134","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,24]]},"article-number":"1459134"}}