{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:43:08Z","timestamp":1790023388531,"version":"4.0.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"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. Neurosci."],"abstract":"<jats:p>\n                    \u201cChronic\u201d periodontitis and its keystone pathogen\n                    <jats:italic>Porphyromonas gingivalis<\/jats:italic>\n                    have repeatedly been associated with Alzheimer\u2019s disease (AD). Pathological hallmarks in AD are brain accumulations of amyloid-beta and neurofibrillary tangles consisting of aggregated and hyperphosphorylated tau. In addition, neuroinflammation induced by\n                    <jats:italic>P. gingivalis<\/jats:italic>\n                    has increasingly been recognized as a factor in the pathogenesis of AD. The present mini-review discusses possible mechanisms for the induction of neuroinflammation by\n                    <jats:italic>P. gingivalis<\/jats:italic>\n                    in AD, involving factors such as pro-inflammatory mediators, amyloid-beta, tau, microglia, cathepsin B, and protein kinase R. Inflammagens of\n                    <jats:italic>P. gingivalis<\/jats:italic>\n                    such as lipopolysaccharide and gingipains are also discussed.\n                  <\/jats:p>","DOI":"10.3389\/fnins.2021.691016","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:46:06Z","timestamp":1634172366000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":41,"title":["Porphyromonas gingivalis-Induced Neuroinflammation in Alzheimer\u2019s Disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Ingar","family":"Olsen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.neuint.2004.07.005","article-title":"Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson\u2019s disease and Huntington\u2019s disease.","volume":"46","author":"Bando","year":"2005","journal-title":"Neurochem. Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"307","DOI":"10.3109\/00207454.2013.833510","article-title":"Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer\u2019s disease.","volume":"124","author":"Cai","year":"2014","journal-title":"Int. J. Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1097\/00001756-200212200-00011","article-title":"Phosphorylation of eukaryotic initiation factor-2-alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer\u2019s disease.","volume":"13","author":"Chang","year":"2002","journal-title":"NeuroReport"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/mp.2016.214","article-title":"Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3\u03b2 kinase: implications for Alzheimer\u2019s disease.","volume":"22","author":"Chu","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2598","DOI":"10.3390\/v4112598","article-title":"dsRNA-dependent protein kinase PKR and its role in stress, signaling and HCV infection.","volume":"4","author":"Dabo","year":"2012","journal-title":"Viruses"},{"key":"B6","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1177\/0022034512453589","article-title":"Porphyromonas gingivalis as a potential community activist.","volume":"91","author":"Darveau","year":"2012","journal-title":"J. Dent. Res."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003492","article-title":"Viral and inflammatory triggers of neurodegenerative diseases.","volume":"4","author":"Deleidi","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/s41435-020-00113-5","article-title":"Tau at the interface between neurodegeneration and neuroinflammation.","volume":"21","author":"Didonna","year":"2020","journal-title":"Genes Immun."},{"key":"B9","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":"B10","doi-asserted-by":"publisher","first-page":"870","DOI":"10.2174\/1567205014666170317113606","article-title":"Impact of cytokines and chemokines on Alzheimer\u2019s disease neuropathological hallmarks.","volume":"14","author":"Domingues","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in Alzheimer\u2019s disease brains: evidence for disease causation and treatment with small-molecule inhibitors.","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. Adv."},{"key":"B12","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1111\/prd.12145","article-title":"Periodontitis prevalence in adults \u2265 65 years of age, in the USA.","volume":"72","author":"Eke","year":"2016","journal-title":"Periodontol. 2000"},{"key":"B13","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/nrmicro2873","article-title":"The keystone-pathogen hypothesis.","volume":"10","author":"Hajishengallis","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"B14","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. Neurosc."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-017-0338-3","article-title":"Restoring synaptic plasticity and memory in mouse models of Alzheimer\u2019s disease by PKR inhibition.","volume":"10","author":"Hwang","year":"2017","journal-title":"Mol. Brain"},{"key":"B16","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":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41514-017-0015-x","article-title":"Periodontitis induced by bacterial infection exacerbates features of Alzheimer\u2019s disease in transgenic mice.","volume":"3","author":"Ishida","year":"2017","journal-title":"NPJ Aging Mech. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease.","volume":"4","author":"Kinney","year":"2018","journal-title":"Alzheimers Dement."},{"key":"B19","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.bj.2018.01.003","article-title":"Tau and neuroinflammation: what impact for Alzheimer\u2019s disease and tauopathies?","volume":"41","author":"Laurent","year":"2018","journal-title":"Biomed. J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.archoralbio.2019.01.008","article-title":"Porphyromonas gingivalis lipopolysaccharide-induced periodontitis and serum amyloid-beta peptides.","volume":"99","author":"Leira","year":"2019","journal-title":"Arch. Oral Biol."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12173-1","article-title":"Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice.","volume":"7","author":"Liu","year":"2017","journal-title":"Sci. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/j.cmet.2013.11.00","article-title":"TNF-\u03b1 mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer\u2019s \u03b2-amyloid oligomers in mice and monkeys.","volume":"18","author":"Lourenco","year":"2013","journal-title":"Cell Metab."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1038\/nn.3486","article-title":"Suppression of eIF2\u03b1 kinases alleviates Alzheimer\u2019s disease-related plasticity and memory deficits.","volume":"16","author":"Ma","year":"2013","journal-title":"Nat. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1096\/fj.13-248294","article-title":"The impact of PKR activation: from neurodegeneration to cancer.","volume":"28","author":"Marchal","year":"2014","journal-title":"FASEB J."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/toxins12050333","article-title":"Classical and alternative activation of rat microglia treated with ultrapure Porphyromonas gingivalis lipopolysaccharide in vitro.","volume":"12","author":"Memedovski","year":"2020","journal-title":"Toxins"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.552","article-title":"PKR downregulation prevents neurodegeneration and \u03b2-amyloid production in a thiamine-deficient model.","volume":"6","author":"Mouton-Liger","year":"2015","journal-title":"Cell Death Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"495","DOI":"10.2174\/1871527319666200708125130","article-title":"Microglial cathepsin B and Porphyromonas gingivalis gingipains as potential therapeutic targets for sporadic Alzheimer\u2019s disease.","volume":"19","author":"Nakanishi","year":"2020","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"B28","doi-asserted-by":"publisher","first-page":"479","DOI":"10.3233\/JAD-190298","article-title":"Porphyromonas gingivalis infection induces amyloid-\u03b2 accumulation in monocytes\/macrophages.","volume":"72","author":"Nie","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2020.104840","article-title":"Secreted gingipains from Porphyromonas gingivalis induce microglia migration through endosomal signaling by protease-activated receptor 2.","volume":"140","author":"Nonaka","year":"2020","journal-title":"Neurochem. Int."},{"key":"B30","doi-asserted-by":"publisher","first-page":"79","DOI":"10.3233\/ADR-200272","article-title":"Porphyromonas gingivalis may seek the Alzheimer\u2019s disease brain to acquire iron from its surplus.","volume":"5","author":"Olsen","year":"2021","journal-title":"J. Alzheimer\u2019s Dis. Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.3233\/JAD-160197","article-title":"Inflammasome involvement in Alzheimer\u2019s disease.","volume":"54","author":"Olsen","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1080\/20002297.2020.1820834","article-title":"Interaction between genetic factors, Porphyromonas gingivalis and microglia to promote Alzheimer\u2019s disease.","volume":"12","author":"Olsen","year":"2020","journal-title":"J. Oral Microbiol."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3402\/jom.v8.30385","article-title":"Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases.","volume":"8","author":"Olsen","year":"2016","journal-title":"J. Oral Microbiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1111\/j.1750-3639.2011.00520.x","article-title":"The PKR activator PACT is induced by A\u03b2: involvement in Alzheimer\u2019s disease.","volume":"22","author":"Paquet","year":"2012","journal-title":"Brain Pathol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1093\/hmg\/10.15.1531","article-title":"Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington\u2019s disease (HD) transcripts and is activated in HD tissue.","volume":"10","author":"Peel","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"B36","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\u2019s disease brain tissue.","volume":"36","author":"Poole","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/bpa.12883","article-title":"PKR kinase directly regulates tau expression and Alzheimer\u2019s disease-related tau phosphorylation.","volume":"31","author":"Reimer","year":"2021","journal-title":"Brain Pathol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.bmcl.2016.11.08","article-title":"Ser422 phosphorylation blocks human Tau cleavage by caspase-3: Biochemical implications to Alzheimer\u2019s disease.","volume":"27","author":"Sandhu","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B39","doi-asserted-by":"publisher","first-page":"12986","DOI":"10.1523\/JNEUROSCI.5241-14.2015","article-title":"PKR inhibition rescues memory deficit and ATF4 overexpression in ApoE \u03b54 human replacement mice.","volume":"35","author":"Segev","year":"2015","journal-title":"J. Neurosci."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111961","article-title":"Usnic acid derivatives as tau-aggregation and neuroinflammation inhibitors.","volume":"187","author":"Shi","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1111\/j.1600-051x.1998.tb02419.x","article-title":"Microbial complexes in subgingival plaque.","volume":"25","author":"Socransky","year":"1998","journal-title":"J. Clin. Periodontol."},{"key":"B42","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":"B43","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":"B44","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-6-26","article-title":"Temporal activation of anti- and pro-apoptotic factors in human gingival fibroblasts infected with the periodontal pathogen, Porphyromonas gingivalis: potential role of bacterial proteases in host signalling.","volume":"6","author":"Urnowey","year":"2006","journal-title":"BMC Microbiol."},{"key":"B45","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\u2019s 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":"B46","doi-asserted-by":"publisher","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":"B47","doi-asserted-by":"publisher","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 Neuroinflammation"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.691016\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:46:11Z","timestamp":1634172371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.691016\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,14]]},"references-count":47,"alternative-id":["10.3389\/fnins.2021.691016"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2021.691016","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,14]]},"article-number":"691016"}}