AbstractDementia is a progressive neurological syndrome characterised by cognitive impairment, in particular with alterations in learning and memory. Alzheimer’s disease and vascular dementia are the two most common forms of this syndrome. Although the pathophysiology of dementia is unknown, changes in several proteins are believed important in its development. These changes could be, to some extent, explained by microRNAs. MicroRNAs are posttranscriptional regulators of gene expression that repress protein synthesis. This thesis attempts to investigate the role of microRNAs in dementia from a more rigorous and biologically relevant perspective. I propose a hypothesis-driven approach considering some factors that have not been taken into account previously. I hypothesise that the levels of certain microRNAs with converging functions would be expressed differently in post-mortem brain tissue of patients diagnosed with Alzheimer’s disease, vascular dementia and non-demented elderly, investigated using novel reference genes and two new formulas proposed to improve microRNA quantification.
A first panel of microRNAs was selected based on their proposed effects on proteins that have been implicated in Alzheimer´s disease. The levels of these microRNAs were significantly different in the Alzheimer’s disease group. A second panel was selected for potential roles on proteins related to hypoxia, vascular dysfunction and the renin angiotensin system. Unexpectedly, no change was observed in the vascular dementia group whilst a statistically significant difference was observed in the Alzheimer´s disease group. Finally, the presence of selected microRNAs was explored in cell culture as potential modelling construct. My results provide new candidates and more rigorous approaches to the study of microRNAs in dementia research. This work will inform future research in the emerging field of microRNAs in dementia whilst also challenging the validity of findings to date.
|Date of Award
|28 Nov 2019
|Patrick Gavin Kehoe (Supervisor) & Shelley J Allen (Supervisor)