{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T09:38:24Z","timestamp":1793093904732,"version":"4.5.0"},"reference-count":35,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"the Science and Technology Commission of Shanghai Municipality","award":["No.22ZR1437500"],"award-info":[{"award-number":["No.22ZR1437500"]}],"id":[{"id":"https:\/\/ror.org\/03kt66j61","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Cross Disciplinary Research Fund of Shanghai Ninth People's Hospital, Shanghai Jiao Tong university School of Medicine","award":["JYJC202225"],"award-info":[{"award-number":["JYJC202225"]}],"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Cross Disciplinary Research Fund of Shanghai Ninth People's Hospital, Shanghai Jiao Tong university School of Medicine","award":["JYJC202308"],"award-info":[{"award-number":["JYJC202308"]}],"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"national natural science foundation of china","doi-asserted-by":"publisher","award":["82071112"],"award-info":[{"award-number":["82071112"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"national natural science foundation of china","doi-asserted-by":"publisher","award":["82270974"],"award-info":[{"award-number":["82270974"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:p>\n                    Periodontitis, caused by periodontal pathogens such as\n                    <jats:italic toggle=\"yes\">Porphyromonas gingivalis<\/jats:italic>\n                    , is a risk factor for Alzheimer\u2019s disease (AD) progression. Neutrophils, which are abundant in patients with periodontitis, release neutrophil extracellular traps (NETs) to resist microbial infection. We explored the mechanism and effects of\n                    <jats:italic toggle=\"yes\">P. gingivalis<\/jats:italic>\n                    \u2013induced NETs on the relationship between periodontitis and neuroinflammation. A murine periodontitis model was established via oral local application of\n                    <jats:italic toggle=\"yes\">P. gingivalis<\/jats:italic>\n                    with or without tak242 (TLR4 inhibitor). Maxillary bones were evaluated via micro\u2013computed tomography. The proportion of neutrophils was determined by flow cytometry. NET formation and morphology were analyzed via a cell-free DNA kit, a neutrophil elastase enzyme-linked immunosorbent assay (ELISA) and myeloperoxidase ELISA kit, reverse transcription polymerase chain reaction (RT-PCR), western blotting and immunofluorescence. Behavior tests were used to investigate cognitive ability. Neuroinflammation was assayed by immunohistochemistry (IHC) and RT-PCR. Amyloid precursor protein (APP) processing was measured by IHC. In vitro experiments explored the functional mechanism underlying the effects of\n                    <jats:italic toggle=\"yes\">P. gingivalis<\/jats:italic>\n                    \u2013induced NETs on the neuron\u2013glia unit. We observed significant alveolar bone resorption with elevated neutrophil count and increased NET formation in mice with periodontitis. Cognitive abilities were impaired by periodontitis. Neuroinflammation manifested as glia activation and upregulated inflammatory cytokines, and APP processing was altered by the elevated expression of APP and PSEN1. These changes were specifically reversed by tak242. In vitro,\n                    <jats:italic toggle=\"yes\">P. gingivalis<\/jats:italic>\n                    \u2013induced NETs mediated M1 polarization in BV2 cells and changed APP processing in N2a cells, along with the activation of TLR4\/Myd88\/NF-\u03baB and GSK3\u03b2\/Akt, which is consistent with the in vivo findings. In conclusion,\n                    <jats:italic toggle=\"yes\">P. gingivalis<\/jats:italic>\n                    \u2013induced NETs play pivotal roles in the relationship between neuroinflammation and cognitive impairment. Furthermore, the effects of\n                    <jats:italic toggle=\"yes\">P. gingivalis<\/jats:italic>\n                    \u2013induced NETs on neuron\u2013glia unit were related to TLR4 activation.\n                  <\/jats:p>","DOI":"10.1177\/00220345261425925","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:58:44Z","timestamp":1782845924000},"page":"1612-1621","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>Porphyromonas gingivalis<\/i>\n                    \u2013Induced NETs Mediate Neuroinflammation via TLR4 Activation"],"prefix":"10.1177","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8540-222X","authenticated-orcid":false,"given":"L.","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Periodontology, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"},{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7534-5748","authenticated-orcid":false,"given":"Y.","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"},{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"},{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"},{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"},{"name":"Laboratory of Oral Microbiota and Systemic Disease, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Li","sequence":"additional","affiliation":[{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"},{"name":"Laboratory of Oral Microbiota and Systemic Disease, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6242-6563","authenticated-orcid":false,"given":"Z.","family":"He","sequence":"additional","affiliation":[{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"},{"name":"Laboratory of Oral Microbiota and Systemic Disease, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"},{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Stomatology, Shanghai Jiao Tong University, Shanghai, China"},{"name":"National Center for Stomatology, Shanghai, China"},{"name":"National Clinical Research Center for Oral Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China"},{"name":"Laboratory of Oral Microbiota and Systemic Disease, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"crossref","unstructured":"Akiyama H et al. 2000. 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Trends Neurosci. 46(9):764\u2013779. https:\/\/doi.org\/10.1016\/j.tins.2023.06.005","DOI":"10.1016\/j.tins.2023.06.005"},{"key":"e_1_3_4_6_1","doi-asserted-by":"crossref","unstructured":"Chu C et al. 2024. Neutrophil extracellular traps aggravate intestinal epithelial necroptosis in ischaemia-reperfusion by regulating TLR4\/RIPK3\/FUNDC1-required mitophagy. Cell Prolif. 57(1):e13538. https:\/\/doi.org\/10.1111\/cpr.13538","DOI":"10.1111\/cpr.13538"},{"key":"e_1_3_4_7_1","doi-asserted-by":"crossref","unstructured":"Ciccotosto GD et al. 2024. Chronic oral inoculation of Porphyromonas gingivalis and Treponema denticola induce different brain pathologies in a mouse model of Alzheimer disease. J Infect Dis. 230(Suppl 2):S109\u2013S116. https:\/\/doi.org\/10.1093\/infdis\/jiae286","DOI":"10.1093\/infdis\/jiae286"},{"key":"e_1_3_4_8_1","doi-asserted-by":"crossref","unstructured":"Collins MS et al. 2023. Heterogeneity in neutrophil extracellular traps from healthy human subjects. 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Sci Adv. 5(1):eaau3333. https:\/\/doi.org\/10.1126\/sciadv.aau3333","DOI":"10.1126\/sciadv.aau3333"},{"key":"e_1_3_4_12_1","doi-asserted-by":"crossref","unstructured":"Ge F et al. 2024. Discovering common pathogenetic processes between periodontitis and Alzheimer\u2019s disease by bioinformatics and system biology approach. BMC Oral Health. 24(1):1074. https:\/\/doi.org\/10.1186\/s12903-024-04775-9","DOI":"10.1186\/s12903-024-04775-9"},{"key":"e_1_3_4_13_1","doi-asserted-by":"crossref","unstructured":"Gour N et al. 2024. A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection. Immunity. 57(2):333\u2013348.e6. https:\/\/doi.org\/10.1016\/j.immuni.2024.01.003","DOI":"10.1016\/j.immuni.2024.01.003"},{"key":"e_1_3_4_14_1","doi-asserted-by":"crossref","unstructured":"Guo H et al. 2023. Oat \u03b2-D-glucan ameliorates type II diabetes through TLR4\/PI3K\/AKT mediated metabolic axis. 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An investigation into the effects of outer membrane vesicles and lipopolysaccharide of Porphyromonas gingivalis on blood-brain barrier integrity permeability and disruption of scaffolding proteins in a human in vitro model. J Alzheimers Dis. 86(1):343\u2013364. https:\/\/doi.org\/10.3233\/jad-215054","DOI":"10.3233\/JAD-215054"},{"key":"e_1_3_4_27_1","doi-asserted-by":"crossref","unstructured":"Rosenzweig N et al. 2024. Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer\u2019s disease. Nat Med. 30(10):2990\u20133003. https:\/\/doi.org\/10.1038\/s41591-024-03122-3","DOI":"10.1038\/s41591-024-03122-3"},{"key":"e_1_3_4_28_1","doi-asserted-by":"crossref","unstructured":"Sangineto M et al. 2023. Metabolic reprogramming in inflammatory microglia indicates a potential way of targeting inflammation in Alzheimer\u2019s disease. 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