Ravey, J;
(2021)
Characterising microtubule-associated protein tau in clinical subtypes of pathologically defined Alzheimer’s disease.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
RAVEY_J_PHD_THESIS_UCL_FINAL_29.11.2021.pdf - Accepted Version Download (172MB) | Preview |
Abstract
Alzheimer’s disease (AD) is recognised as the most common disease prompting the development of dementia, a leading cause of death in an increasing number of countries around the world. As it stands, there are no effective therapeutics to lessen or treat AD and with diagnoses predicted to rise year on year, there is an urgent need for greater understanding of the pathogenic mechanisms underlying the condition. Diagnosis of AD relies heavily on the presence of senile plaque and neurofibrillary pathologies in the brain at post-mortem. However, within AD patient populations, an abundance of heterogeneity is observed regarding clinical features. It has been proposed the proteins underlying the AD-related pathologies – Aβ and tau – could vary in their activity across AD patients, contributing towards these observed differences. In particular, the existence of tau ‘strains’ has gained traction due to the proteins dysfunction in a range of neurodegenerative conditions. We set out to study if tau pathology in AD varies based on clinical subtype. Using a pilot group of AD subtype brains, we established an array of assays to detect disease-associated tau based on methods used in prion diseases; a group of conditions characterised by distinct biological strains of prion protein assemblies or prions. In our pilot group, we found no subtype-specific tau signature, but levels of disease-associated tau were heterogeneous in atypical AD brains. Furthermore, we reported successful induction of tau pathology in several knock-in mouse models following inoculation with typical AD homogenates - seemingly influenced by Aβ levels and expression of human tau – which was less robust following atypical AD homogenate inoculation. Finally, we established a human neuronal activity assay which we plan to use to discriminate tau-associated infectivity and toxicity in future studies. These results lay the foundations for large scale investigations into the existence of tau strains within AD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Characterising microtubule-associated protein tau in clinical subtypes of pathologically defined Alzheimer’s disease |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. 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. |
| Keywords: | Alzheimer's disease, Microtubule-associated protein tau, Alzheimer's disease subtypes |
| UCL classification: | UCL 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10139308 |
Archive Staff Only
 |
View Item |
