Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/4177
Full metadata record
DC FieldValueLanguage
dc.contributor.authorFielder, Edward Peter-
dc.date.accessioned2019-02-05T12:08:38Z-
dc.date.available2019-02-05T12:08:38Z-
dc.date.issued2018-
dc.identifier.urihttp://hdl.handle.net/10443/4177-
dc.descriptionPhD Thesisen_US
dc.description.abstractSenescent cells accumulate in the body with age, and drive organismal ageing and tissue dysfunction. Senescence is not a simple growth arrest, but is accompanied by a host of phenotypic changes, including the generation of pro-inflammatory molecules, and is maintained by a network of auto- and paracrine reinforcement. Senescence is now also understood to occur in post-mitotic cells, including neurons – contrary to the former definition of senescence occurring exclusively in proliferating cells. This is called the senescent-like phenotype. While senescent cells can be seen to increase with age, little is known about their relation to cognitive function with age or pathological states such neuro-inflammation. Using a model of chronic inflammation, the nfkb1-/- mouse, I investigated neuro-inflammation, cognitive function and the frequency of senescent-like neurons with age and treatment with the COX-2 inhibitor ibuprofen. Increasing microglial proliferation and neuro-inflammation could be observed, together with deficits in spatial memory. This was accompanied by an increase in the numbers of senescent-like neurons. Increased accumulation of persistent DNA damage in pyramidal neurons, and a deficit in the generation and propagation of Carbachol induced gamma frequency oscillations, could be seen in the CA3. COX-2 appears to have a role in mediating these effects, as treatment with ibuprofen was effective in ameliorating levels of neuro-inflammation, cognitive dysfunction and senescent-like neurons. Ageing INK-ATTAC mice were given pharmacogenetic and pharmacological treatments to investigate if these could clear senescent-like neurons. Pharmacological clearance (Dasatinib and Quercetin) was effective in reducing the numbers of senescent like neurons, and these mice showed an improvement in cognitive function, while pharmacogenetic treatment had a lesser effect. The data presented in this thesis implicate the senescence and the senescent-like phenotype in neuro-inflammation and ageing, and in driving the accompanying declines in cognitive function.en_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleDoes a senescene-like phenotype in neurons contribute to brain ageing and neurodegeneration?en_US
dc.typeThesisen_US
Appears in Collections:Institute for Ageing and Health

Files in This Item:
File Description SizeFormat 
Fielder, E.P. 2018.pdfThesis9.01 MBAdobe PDFView/Open
dspacelicence.pdfLicence43.82 kBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.