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dc.contributor.authorLynch, Marina
dc.contributor.authorKerskens, Christian
dc.contributor.authorMcIntosh, Allison
dc.contributor.authorMela, Virginia
dc.contributor.authorHarty, Conor
dc.contributor.authorMinogue, Aedin M.
dc.contributor.authorCostello, Derek A.
dc.contributor.authorKerskens, Christian
dc.contributor.authorLynch, Marina A.
dc.date.accessioned2019-11-22T15:28:30Z
dc.date.available2019-11-22T15:28:30Z
dc.date.issued2019
dc.date.submitted2019en
dc.identifier.citationMcIntosh, A., Mela, V., Harty, C., Minogue, A.M., Costello, D.A., Kerskens, C. & Lynch, M.A., Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice., Brain Pathology, 2019, 29, 5, 10.1111/bpa.12704.en
dc.identifier.otherY
dc.identifier.urihttps://onlinelibrary.wiley.com/doi/full/10.1111/bpa.12704
dc.identifier.urihttp://hdl.handle.net/2262/90854
dc.descriptionPUBLISHEDen
dc.description.abstractAmong the changes that typify Alzheimer’s disease (AD) are neuroinflammation and microglial activation, amyloid deposition perhaps resulting from compromised microglial function and iron accumulation. Data from Genome Wide Association Studies (GWAS) identified a number of gene variants that endow a significant risk of developing AD and several of these encode proteins expressed in microglia and proteins that are implicated in the immune response. This suggests that neuroinflammation and the accompanying microglial activation are likely to contribute to the pathogenesis of the disease. The trigger(s) leading to these changes remain to be identified. In this study, we set out to examine the link between the inflammatory, metabolic and iron‐retentive signature of microglia in vitro and in transgenic mice that overexpress the amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice), a commonly used animal model of AD. Stimulation of cultured microglia with interferon (IFN)γ and amyloid‐β (Aβ) induced an inflammatory phenotype and switched the metabolic profile and iron handling of microglia so that the cells became glycolytic and iron retentive, and the phagocytic and chemotactic function of the cells was reduced. Analysis of APP/PS1 mice by magnetic resonance imaging (MRI) revealed genotype‐related hypointense areas in the hippocampus consistent with iron deposition, and immunohistochemical analysis indicated that the iron accumulated in microglia, particularly in microglia that decorated Aβ deposits. Isolated microglia prepared from APP/PS1 mice were characterized by a switch to a glycolytic and iron‐retentive phenotype and phagocytosis of Aβ was reduced in these cells. This evidence suggests that the switch to glycolysis in microglia may kick‐start a cascade of events that ultimately leads to microglial dysfunction and Aβ accumulation.en
dc.format.extent10.1111/bpa.12704.en
dc.language.isoenen
dc.relation.ispartofseriesBrain Pathology;
dc.relation.ispartofseries;29
dc.relation.ispartofseries;5
dc.rightsYen
dc.subjectGlycolysisen
dc.subjectIronen
dc.subjectMicrogliaen
dc.subjectamyloid‐β (Aβ)en
dc.subjectNeuroinflammationen
dc.subjectPhagocytosisen
dc.subjectAPP/PS1 miceen
dc.titleIron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice.en
dc.typeJournal Articleen
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/lynchma
dc.identifier.peoplefinderurlhttp://people.tcd.ie/kerskenc
dc.identifier.rssinternalid196687
dc.identifier.doihttp://dx.doi.org/10.1111/bpa.12704
dc.rights.ecaccessrightsopenAccess
dc.subject.TCDThemeAgeingen
dc.subject.TCDThemeNeuroscienceen
dc.subject.TCDTagAlzheimer's diseaseen
dc.status.accessibleNen


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