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dc.contributor.authorBrown, Guyen
dc.date.accessioned2019-08-30T23:30:25Z
dc.date.available2019-08-30T23:30:25Z
dc.date.issued2019-09-13en
dc.identifier.issn1742-2094
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/296293
dc.description.abstractThe endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin, and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid  and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer’s disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer’s disease. Intestinal permeability increases early in Parkinson’s disease, and injection of endotoxin into mice induces -synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson’s disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.
dc.description.sponsorshipWellcome Trust (Grant RG50995) Medical Research Council UK (Grant MR/L010593) Alzheimer’s Research UK European Union (IMI2 grant 115976 -PHAGO)
dc.format.mediumElectronicen
dc.languageengen
dc.publisherBioMed Central
dc.rightsAll rights reserved
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectNeurodegenerative Diseasesen
dc.subjectNerve Degenerationen
dc.subjectEndotoxinsen
dc.titleThe endotoxin hypothesis of neurodegeneration.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameJournal of neuroinflammationen
prism.startingPage180
prism.volume16en
dc.identifier.doi10.17863/CAM.43339
dcterms.dateAccepted2019-08-27en
rioxxterms.versionofrecord10.1186/s12974-019-1564-7en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-09-13en
dc.contributor.orcidBrown, Guy [0000-0002-3610-1730]
dc.identifier.eissn1742-2094
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (084645/Z/08/Z)
pubs.funder-project-idMRC (MR/L010593/1)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Research Infrastructures (RI) (115976)
pubs.funder-project-idAlzheimer's Research UK (ARUK-DC2017-4)
rioxxterms.freetoread.startdate2020-09-30


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