Inflammation is implicated in a wide array of diseases and is associated with the ageing process: 'inflammageing' is the low-grade inflammation that occurs as an organism ages. I was particularly interested in age-related inflammation of the brain, thought to be mediated by microglia, the immune cells of the central nervous system (CNS). To this end, I carried out RNA sequencing of microglia from young (6 months) and aged mice (23 months). I found that microglia from aged mice have a very distinct transcriptome signature. Interestingly, pathways associated with mTOR signalling and inflammation were upregulated. Given the evidence that mTOR is a key modulator of ageing, I investigated its role in inflammation in microglia. Using a mouse model in which Rheb, a positive regulator of mTORC1, was knocked out in Csf1r-expressing cells (microglia and macrophages), I found that in vivo LPS stimulation caused a significant increase in the transcription of inflammatory genes in microglia from mTORC1-deficient mice compared to controls. The effect was further exaggerated in mTORC1-deficient aged mice, suggesting a role for mTORC1 in the priming of aged microglia. However, these transcriptome changes were not translated into protein; indeed, Csf1r-Cre; Rheb f/f mice showed reduced overall inflammation, as measured by sickness behaviour in the openfield test and by plasma cytokine levels. On the other hand, long-term treatment with rapamycin in vivo showed a very distinct phenotype, with reduced inflammation following LPS stimulation in young mice but no effect in aged ones. This PhD thesis sheds new light on pathways regulating microglia in ageing and has clinical implications for pathologies in which inflammation plays a major role.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:765800 |
| Date | January 2016 |
| Creators | Keane, Lily |
| Publisher | Queen Mary, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://qmro.qmul.ac.uk/xmlui/handle/123456789/23220 |
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