Alzheimer's Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active Gingipains

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dc.contributor.authorHaditsch, Ursulaen
dc.contributor.authorRoth, Theresaen
dc.contributor.authorRodriguez, Leoen
dc.contributor.authorHancock, Sandyen
dc.contributor.authorCecere, Thomas E.en
dc.contributor.authorNguyen, Maien
dc.contributor.authorArastu-Kapur, Shirinen
dc.contributor.authorBroce, Seanen
dc.contributor.authorRaha, Debasishen
dc.contributor.authorLynch, Casey C.en
dc.contributor.authorHolsinger, Leslie J.en
dc.contributor.authorDominy, Stephen S.en
dc.contributor.authorErmini, Florianen
dc.date.accessioned2021-10-05T16:50:33Zen
dc.date.available2021-10-05T16:50:33Zen
dc.date.issued2020-01-01en
dc.date.updated2021-10-05T16:50:29Zen
dc.description.abstractBackground: Porphyromonas gingivalis (P. gingivalis) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer's disease (AD). In a recent study we demonstrated the presence of gingipains in over 90% of postmortem AD brains, with gingipains localizing to the cytoplasm of neurons. However, infection of neurons by P. gingivalis has not been previously reported. Objective: To demonstrate intraneuronal P. gingivalis and gingipain expression in vitro after infecting neurons derived from human inducible pluripotent stem cells (iPSC) with P. gingivalis for 24, 48, and 72 h. Methods: Infection was characterized by transmission electron microscopy, confocal microscopy, and bacterial colony forming unit assays. Gingipain expression was monitored by immunofluorescence and RT-qPCR, and protease activity monitored with activity-based probes. Neurodegenerative endpoints were assessed by immunofluorescence, western blot, and ELISA. Results: Neurons survived the initial infection and showed time dependent, infection induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons displayed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was strongly degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons was decreased. Conclusion: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho-tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches.en
dc.description.versionPublished versionen
dc.format.extentPages 1361-1376en
dc.format.extent16 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3233/JAD-200393en
dc.identifier.eissn1875-8908en
dc.identifier.issn1387-2877en
dc.identifier.issue4en
dc.identifier.orcidCecere, Thomas [0000-0001-9558-0615]en
dc.identifier.otherJAD200393 (PII)en
dc.identifier.pmid32390638en
dc.identifier.urihttp://hdl.handle.net/10919/105167en
dc.identifier.volume75en
dc.language.isoenen
dc.publisherIOS Pressen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000550022100026&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectNeurosciencesen
dc.subjectNeurosciences & Neurologyen
dc.subjectAlzheimer's diseaseen
dc.subjectgingipain cysteine endopeptidasesen
dc.subjectin vitro techniquesen
dc.subjectmultivesicular bodiesen
dc.subjectPorphyromonasen
dc.subjectgingivalisen
dc.subjectsynapsesen
dc.subjecttau proteinen
dc.subjectTOOTH LOSSen
dc.subjectTAUen
dc.subjectAUTOPHAGYen
dc.subjectACTIVATIONen
dc.subjectINVASIONen
dc.subjectOXYGENen
dc.subjectPHOSPHORYLATIONen
dc.subjectMICROTUBULESen
dc.subjectTRANSPORTen
dc.subjectBACTERIAen
dc.subject1103 Clinical Sciencesen
dc.subject1109 Neurosciencesen
dc.subject1702 Cognitive Sciencesen
dc.subject.meshNeuronsen
dc.subject.meshCells, Cultureden
dc.subject.meshAnimalsen
dc.subject.meshMiceen
dc.subject.meshPorphyromonas gingivalisen
dc.subject.meshBacteroidaceae Infectionsen
dc.subject.meshAlzheimer Diseaseen
dc.subject.meshNeural Stem Cellsen
dc.subject.meshGingipain Cysteine Endopeptidasesen
dc.titleAlzheimer's Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active Gingipainsen
dc.title.serialJournal of Alzheimers Diseaseen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten

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