Mistry, Beenaben Narendrakumar;
(2024)
Examining the Interactions of Amyloid-Beta and Tau with the Cellular Prion Protein.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the United Kingdom. Whilst treatments are available to improve the symptoms associated with AD, the lack of preventative measures for the disease and an increase in life expectancy is contributing to a steep rise in the number of patients living with AD each year. As such, the fundamental biological processes behind the disease must be examined to allow for the development of successful therapeutics. We set out to investigate the cellular prion protein (PrPC)-dependent molecular mechanisms and associated changes that occur after inoculation of human AD brain homogenates into multiple knock-in mouse models that express humanised amyloid-beta (Aβ) and/or humanised tau with varying levels of PrPC. We used an array of assays to examine the biochemical and histopathological changes that occur in these mice at multiple predetermined time points. Whilst overexpression of PrPC was found to not affect the levels of soluble Aβ and the spatiotemporal deposition of insoluble Aβ, PrPC-overexpressing mice inoculated with human AD brain homogenates had higher levels of Fyn and Pyk2 phosphorylation at 8 and 12 months post-inoculation, when compared to mice which did not express PrPC. We went on to develop a murine neuronal assay based on these findings to further understand the interactions of oligomeric Aβ and PrPC. Finally, we performed behavioural, biochemical, and histopathological experiments to understand the effect of PrPC expression in a tau transgenic mouse model. We reported changes in motor coordination, sarkosyl-insoluble tau and disease-associated tau levels, which were closely related to PrPC expression levels in the transgenic mice. Together, these results continue to unravel the molecular interactions of Aβ and tau with PrPC in AD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Examining the Interactions of Amyloid-Beta and Tau with the Cellular Prion Protein |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10185281 |
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