{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T16:02:13Z","timestamp":1793808133187,"version":"4.6.1"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"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. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>Porphyromonas gingivalis<\/jats:italic> (Pg), the keystone pathogen in chronic periodontitis, is reported to initiate Alzheimer\u2019s disease pathologies in preclinical studies. However, the specific mechanisms and signaling pathways acting on the brain still need to be further explored. Outer membrane vesicles are derived from Gram-negative bacteria and contain many virulence factors of bacteria. We hypothesized that outer membrane vesicles are an important weapon of <jats:italic>Porphyromonas gingivalis<\/jats:italic> to initiate Alzheimer\u2019s disease pathologies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The outer membrane vesicles of <jats:italic>Porphyromonas gingivalis<\/jats:italic> (Pg OMVs, 4 mg\/kg) or saline were delivered to 14-month-old mice by oral gavage every other day for eight weeks. Behavioral alterations were assessed by the open field test, Morris water maze, and Y-maze test. Blood\u2013brain barrier permeability, neuroinflammation, tau phosphorylation, and NLRP3 inflammasome-related protein were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pg OMVs impaired memory and learning ability of mice and decreased tight junction\u2013related gene expression ZO-1, occludin, claudin-5, and occludin protein expression in the hippocampus. Pg OMVs could be detected in the hippocampus and cortex three days after oral gavage. Furthermore, Pg OMVs activated both astrocytes and microglia and elevated IL-1\u03b2, tau phosphorylation on the Thr231 site, and NLRP3 inflammasome\u2013related protein expression in the hippocampus. In <jats:italic>in vitro<\/jats:italic> studies, Pg OMV (5 \u00b5g\/ml) stimulation increased the mRNA and immunofluorescence of NLRP3 in BV2 microglia, which were significantly inhibited by the NLRP3 inhibitor MCC950. In contrast, the tau phosphorylation in N2a neurons was enhanced after treatment with conditioned media from Pg OMV-stimulated microglia, which was attenuated after pretreatment with MCC950.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results indicate that Pg OMVs prompt memory dysfunction, neuroinflammation, and tau phosphorylation and trigger NLRP3 inflammasome in the brain of middle-aged mice. We propose that Pg OMVs play an important role in activating neuroinflammation in the AD-like pathology triggered by <jats:italic>Porphyromonas gingivalis<\/jats:italic>, and NLRP3 inflammasome activation is a possible mechanism.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.925435","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T05:44:13Z","timestamp":1660023853000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":143,"title":["Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Ting","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchen","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deqin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/BF02815005","article-title":"Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease","author":"Alvarez","year":"1996","journal-title":"Mol. Chem. Neuropathol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/j.micinf.2010.05.008","article-title":"Outer membrane vesicles function as offensive weapons in host-parasite interactions","volume":"12","author":"Amano","year":"2010","journal-title":"Microbes Infect."},{"key":"B3","doi-asserted-by":"publisher","first-page":"5480","DOI":"10.1523\/JNEUROSCI.0200-20.2020","article-title":"Enduring changes in neuronal function upon systemic inflammation are NLRP3 inflammasome dependent","volume":"40","author":"Beyer","year":"2020","journal-title":"J. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12159","article-title":"Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo","volume":"10","author":"Bittel","year":"2021","journal-title":"J. Extracell Vesicles."},{"key":"B5","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1902\/jop.2007.060078","article-title":"Comparison of subgingival bacterial sampling with oral lavage for detection and quantification of periodontal pathogens by real-time polymerase chain reaction","volume":"78","author":"Boutaga","year":"2007","journal-title":"J. Periodontol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.3233\/JAD-180098","article-title":"Role of blood-brain barrier in alzheimer's disease","volume":"63","author":"Cai","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01017","article-title":"Outer membrane vesicles prime and activate macrophage inflammasomes and cytokine secretion In vitro and In vivo","volume":"8","author":"Cecil","year":"2017","journal-title":"Front. Immunol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.755925","article-title":"Porphyromonas gingivalis induced cognitive impairment is associated with gut dysbiosis, neuroinflammation, and glymphatic dysfunction","volume":"11","author":"Chi","year":"2021","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1177\/0022034512453589","article-title":"Porphyromonas gingivalis as a potential community activist for disease","author":"Darveau","year":"2012","journal-title":"J. Dent. Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1111\/j.1468-1331.2008.02252.x","article-title":"Cytokine IL-1 beta but not IL-1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the canary islands, Spain","volume":"15","author":"Deniz-Naranjo","year":"2008","journal-title":"Eur. J. Neurol."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/s12979-017-0110-7","article-title":"Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice","volume":"15","author":"Ding","year":"2018","journal-title":"Immun. Ageing."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. Adv."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.26355\/eurrev_201903_17218","article-title":"Microbes and alzheimer' disease: lessons from h. pylori and GUT microbiota","volume":"23","author":"Doulberis","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00195","article-title":"16S rRNA next generation sequencing analysis shows bacteria in alzheimer's post-mortem brain","volume":"9","author":"Emery","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00351","article-title":"Metabolic remodeling, inflammasome activation, and pyroptosis in macrophages stimulated by Porphyromonas gingivalis and its outer membrane vesicles","volume":"7","author":"Fleetwood","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/ni.2913","article-title":"The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation","volume":"15","author":"Franklin","year":"2014","journal-title":"Nat. Immunol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10112358","article-title":"The microbiota-Gut-Brain axis and Alzheimer disease. from dysbiosis to neurodegeneration: Focus on the central nervous system glial cells","volume":"10","author":"Giovannini","year":"2021","journal-title":"J. Clin. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/s0531-5565(00)00110-8","article-title":"The pervasiveness of interleukin-1 in alzheimer pathogenesis: a role for specific polymorphisms in disease risk","volume":"35","author":"Griffin","year":"2000","journal-title":"Exp. Gerontol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1111\/omi.12134","article-title":"Spheres of influence: Porphyromonas gingivalis outer membrane vesicles","volume":"31","author":"Gui","year":"2016","journal-title":"Mol. Oral. Microbiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3233\/JAD-200689","article-title":"Systemic exposure to lipopolysaccharide from Porphyromonas gingivalis induces bone loss-correlated alzheimer's disease-like pathologies in middle-aged mice","volume":"78","author":"Gu","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2020.596366","article-title":"Delivery of periodontopathogenic extracellular vesicles to brain monocytes and microglial IL-6 promotion by RNA cargo","volume":"7","author":"Ha","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"13412","DOI":"10.1096\/fj.201901575R","article-title":"Extracellular RNAs in periodontopathogenic outer membrane vesicles promote TNF-alpha production in human macrophages and cross the blood-brain barrier in mice","volume":"33","author":"Han","year":"2019","journal-title":"FASEB J."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.816640","article-title":"Periodontal infection aggravates C1q-mediated microglial activation and synapse pruning in alzheimer\u2019s mice","volume":"13","author":"Hao","year":"2022","journal-title":"Front. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.exger.2019.02.007","article-title":"Continuous intracerebroventricular injection of Porphyromonas gingivalis lipopolysaccharide induces systemic organ dysfunction in a mouse model of alzheimer's disease","volume":"120","author":"Hayashi","year":"2019","journal-title":"Exp. Gerontol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1007\/s00784-011-0654-4","article-title":"Quantitative analysis of microbiota in saliva, supragingival, and subgingival plaque of Chinese adults with chronic periodontitis","volume":"16","author":"He","year":"2012","journal-title":"Clin. Oral. Investig."},{"key":"B27","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in alzheimer's disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nature11729","article-title":"NLRP3 is activated in alzheimer's disease and contributes to pathology in APP\/PS1 mice","volume":"493","author":"Heneka","year":"2013","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123448","article-title":"Functional advantages of Porphyromonas gingivalis vesicles","volume":"10","author":"Ho","year":"2015","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2016.00139","article-title":"Characterization of innate immune responses of human endothelial cells induced by Porphyromonas gingivalis and their derived outer membrane vesicles","volume":"6","author":"Ho","year":"2016","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00658","article-title":"Periodontitis induced by p. gingivalis-LPS is associated with neuroinflammation and learning and memory impairment in sprague-dawley rats","volume":"14","author":"Hu","year":"2020","journal-title":"Front. Neurosci."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0204941","article-title":"Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice","volume":"13","author":"Ilievski","year":"2018","journal-title":"PloS One"},{"key":"B33","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":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbi.2021.08.213","article-title":"GSK3beta is involved in promoting alzheimer's disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor protein(NL-F\/NL-F) knock-in mice","volume":"98","author":"Jiang","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00460-18","article-title":"Oral administration of Porphyromonas gingivalis alters the gut microbiome and serum metabolome","volume":"3","author":"Kato","year":"2018","journal-title":"mSphere"},{"key":"B36","doi-asserted-by":"publisher","first-page":"4067","DOI":"10.1111\/febs.13412","article-title":"The dynamic blood-brain barrier","volume":"282","author":"Keaney","year":"2015","journal-title":"FEBS J."},{"key":"B37","doi-asserted-by":"publisher","first-page":"6539","DOI":"10.4049\/jimmunol.1100620","article-title":"Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an alzheimer's disease model","volume":"187","author":"Kitazawa","year":"2011","journal-title":"J. Immunol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"708","DOI":"10.2174\/156720510793611556","article-title":"Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in alzheimer's disease","volume":"7","author":"Kovacech","year":"2010","journal-title":"Curr. Alzheimer Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s40168-020-00881-2","article-title":"The extracellular vesicle of gut microbial paenalcaligenes hominis is a risk factor for vagus nerve-mediated cognitive impairment","volume":"8","author":"Lee","year":"2020","journal-title":"Microbiome"},{"key":"B40","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.brainres.2017.06.014","article-title":"Early-life lipopolysaccharide exposure potentiates forebrain expression of NLRP3 inflammasome proteins and anxiety-like behavior in adolescent rats","volume":"1671","author":"Lei","year":"2017","journal-title":"Brain Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41582-019-0299-5","article-title":"NEURODEGENERATIVE DISEASE NLRP3 inflammasome activation implicated in tau pathology","volume":"16","author":"Lempriere","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1002\/mbo3.221","article-title":"Fimbriae-mediated outer membrane vesicle production and invasion of Porphyromonas gingivalis","volume":"4","author":"Mantri","year":"2015","journal-title":"Microbiologyopen"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134234","article-title":"Oral administration of p. gingivalis induces dysbiosis of gut microbiota and impaired barrier function leading to dissemination of enterobacteria to the liver","volume":"10","author":"Nakajima","year":"2015","journal-title":"PloS One"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.3233\/JAD-210448","article-title":"Porphyromonas gingivalis outer membrane vesicles as the major driver of and explanation for neuropathogenesis, the cholinergic hypothesis, iron dyshomeostasis, and salivary lactoferrin in alzheimer's disease","volume":"82","author":"Nara","year":"2021","journal-title":"J. Alzheimers Dis"},{"key":"B45","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s40478-018-0557-6","article-title":"Phosphorylation of different tau sites during progression of alzheimer's disease","volume":"6","author":"Neddens","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"479","DOI":"10.3233\/JAD-190298","article-title":"Porphyromonas gingivalis infection induces amyloid-beta accumulation in Monocytes\/Macrophages","volume":"72","author":"Nie","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114959","article-title":"Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease","volume":"9","author":"Noble","year":"2014","journal-title":"PloS One"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2022.105282","article-title":"Secreted gingipains from Porphyromonas gingivalis increase permeability in human cerebral microvascular endothelial cells through intracellular degradation of tight junction proteins","volume":"154","author":"Nonaka","year":"2022","journal-title":"Neurochem. Int."},{"key":"B49","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1111\/j.1582-4934.2007.00074.x","article-title":"Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist","volume":"11","author":"Oprica","year":"2007","journal-title":"J. Cell Mol. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/S0079-6123(07)63020-9","article-title":"Pro-inflammatory cytokines and their effects in the dentate gyrus","volume":"163","author":"Pickering","year":"2007","journal-title":"Dentate. Gyrus.: A Comphrehens. Guide. To. Struct. Function. Clin. Implicat."},{"key":"B51","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1093\/nutrit\/nuw023","article-title":"Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease","volume":"74","author":"Pistollato","year":"2016","journal-title":"Nutr. Rev."},{"key":"B52","doi-asserted-by":"publisher","first-page":"665","DOI":"10.3233\/JAD-121918","article-title":"Determining the presence of periodontopathic virulence factors in short-term postmortem alzheimer's disease brain tissue","volume":"36","author":"Poole","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"B53","doi-asserted-by":"publisher","first-page":"343","DOI":"10.3233\/JAD-215054","article-title":"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","volume":"86","author":"Pritchard","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.3233\/JAD-201007","article-title":"Periodontitis deteriorates cognitive function and impairs neurons and glia in a mouse model of alzheimer's disease","volume":"79","author":"Qian","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22168697","article-title":"Immunohistochemical study of ASC expression and distribution in the hippocampus of an aged murine model of alzheimer's disease","volume":"22","author":"Reimers","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"S45","DOI":"10.1002\/JPER.20-0104","article-title":"Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies","author":"Ryder","year":"2020","journal-title":"J. Periodontol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1111\/j.1600-0765.2010.01335.x","article-title":"Salivary infectious agents and periodontal disease status","volume":"46","author":"Saygun","year":"2011","journal-title":"J. Periodontal. Res."},{"key":"B58","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1159\/000346770","article-title":"Bacterial outer membrane vesicles in trafficking, communication and the host-pathogen interaction","volume":"23","author":"Schertzer","year":"2013","journal-title":"J. Mol. Microbiol. Biotechnol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165731","article-title":"Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver","volume":"1866","author":"Seyama","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Bas. Dis."},{"key":"B61","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1006\/exnr.2000.7393","article-title":"Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo","volume":"163","author":"Sheng","year":"2000","journal-title":"Exp. Neurol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"219","DOI":"10.3233\/adr-180080","article-title":"Are Porphyromonas gingivalis outer membrane vesicles microbullets for sporadic alzheimer's disease manifestation","volume":"2","author":"Singhrao","year":"2018","journal-title":"J. Alzheimers Dis. Rep."},{"key":"B63","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.jalz.2011.04.006","article-title":"Serum antibodies to periodontal pathogens are a risk factor for alzheimer's disease","volume":"8","author":"Sparks Stein","year":"2012","journal-title":"Alzheimers Dement."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1007\/s12031-021-01827-5","article-title":"Oral treponema denticola infection induces a beta(1-40) and a beta(1-42) accumulation in the hippocampus of C57BL\/6 mice","volume":"71","author":"Su","year":"2021","journal-title":"J. Mol. Neurosci."},{"key":"B66","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s12031-020-01629-1","article-title":"Effects of Porphyromonas gingivalis and its underlying mechanisms on Alzheimer-like tau hyperphosphorylation in sprague-dawley rats","volume":"71","author":"Tang","year":"2021","journal-title":"J. Mol. Neurosci."},{"key":"B65","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1007\/s12035-013-8475-x","article-title":"The NLRP3 inflammasome in alzheimer's disease","volume":"48","author":"Tan","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41579-018-0112-2","article-title":"Types and origins of bacterial membrane vesicles","volume":"17","author":"Toyofuku","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41583-019-0240-3","article-title":"Amyloid-beta-independent regulators of tau pathology in Alzheimer disease","volume":"21","author":"van der Kant","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"B69","doi-asserted-by":"publisher","first-page":"4843","DOI":"10.1002\/jcp.29362","article-title":"Outer membrane vesicles enhance tau phosphorylation and contribute to cognitive impairment","volume":"235","author":"Wei","year":"2020","journal-title":"J. Cell Physiol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.immuni.2013.08.037","article-title":"Mechanisms of NOD-like receptor-associated inflammasome activation","volume":"39","author":"Wen","year":"2013","journal-title":"Immunity"},{"key":"B71","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.bbi.2017.06.002","article-title":"Cathepsin b plays a critical role in inducing alzheimer's disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice","volume":"65","author":"Wu","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113176","article-title":"Chronic periodontitis induces microbiota-gut-brain axis disorders and cognitive impairment in mice","volume":"326","author":"Xue","year":"2020","journal-title":"Exp. Neurol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s12974-017-1052-x","article-title":"Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL\/6 mice","volume":"15","author":"Zhang","year":"2018","journal-title":"J. Neuroinflammat."},{"key":"B74","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1038\/nrm.2016.80","article-title":"Tight junctions: from simple barriers to multifunctional molecular gates","volume":"17","author":"Zihni","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.925435\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T05:44:16Z","timestamp":1660023856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.925435\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,9]]},"references-count":74,"alternative-id":["10.3389\/fcimb.2022.925435"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.925435","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,9]]},"article-number":"925435"}}