Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.765373
Title: Does a senescene-like phenotype in neurons contribute to brain ageing and neurodegeneration?
Author: Fielder, Edward Peter
ISNI:       0000 0004 7660 2681
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2018
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Abstract:
Senescent 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.765373  DOI: Not available
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