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Living Neurons with Tau Filaments Aberrantly Expose Phosphatidylserine and Are Phagocytosed by Microglia.

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dc.contributor.authorBrelstaff, Jack
dc.contributor.authorTolkovsky, Aviva M
dc.contributor.authorGhetti, Bernardino
dc.contributor.authorGoedert, Michel
dc.contributor.authorSpillantini, Maria Grazia
dc.contributor.orcidBrelstaff, Jack [0000-0003-4772-8018]
dc.contributor.orcidSpillantini, Maria [0000-0002-8544-7332]
dc.date.accessioned2018-10-03T04:43:39Z
dc.date.available2018-10-03T04:43:39Z
dc.date.issued2018-08-21
dc.description.abstractTau protein forms insoluble filamentous inclusions that are closely associated with nerve cell death in many neurodegenerative diseases. How neurons die in these tauopathies is unclear. We report that living neurons with tau inclusions from P301S-tau mice expose abnormally high amounts of phosphatidylserine because of the production of reactive oxygen species (ROS). Consequently, co-cultured phagocytes (BV2 cells or primary microglia) identify and phagocytose the living neurons, thereby engulfing insoluble tau inclusions. To facilitate engulfment, neurons induce contacting microglia to secrete the opsonin milk-fat-globule EGF-factor-8 (MFGE8) and nitric oxide (NO), whereas neurons with tau inclusions are rescued when MFGE8 or NO production is prevented. MFGE8 expression is elevated in transgenic P301S-tau mouse brains with tau inclusions and in tau inclusion-rich brain regions of several human tauopathies, indicating shared mechanisms of disease. Preventing phagocytosis of living neurons will preserve them for treatments that inhibit tau aggregation and toxicity.
dc.format.mediumPrint
dc.identifier.doi10.17863/CAM.25907
dc.identifier.eissn2211-1247
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283030
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.celrep.2018.07.072
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMFGE8
dc.subjectcell death
dc.subjectmicroglia
dc.subjectneurodegeneration
dc.subjectneuroinflammation
dc.subjectnitric oxide
dc.subjectphagocytosis
dc.subjectphosphatidylserine
dc.subjecttau
dc.subjecttauopathies
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMicroglia
dc.subjectNeurons
dc.subjectPhagocytosis
dc.subjectPhosphatidylserines
dc.subjecttau Proteins
dc.titleLiving Neurons with Tau Filaments Aberrantly Expose Phosphatidylserine and Are Phagocytosed by Microglia.
dc.typeArticle
dcterms.dateAccepted2018-07-21
prism.endingPage1948.e4
prism.issueIdentifier8
prism.publicationDate2018
prism.publicationNameCell Rep
prism.startingPage1939
prism.volume24
pubs.funder-project-idNational Centre for the Replacement Refinement and Reduction of Animals in Research (NC/L000741/1)
pubs.funder-project-idAlzheimer's Research UK (ARUK-RF2017A-4)
pubs.funder-project-idWellcome Trust (100574/Z/12/Z)
rioxxterms.licenseref.startdate2018-08
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.celrep.2018.07.072

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