Stuart, Skye;
(2025)
Modulating trans-synaptic tau transfer in vitro and in vivo.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The spatiotemporal spread of pathological tau observed across anatomically connected brain areas in Alzheimer’s disease and other tauopathies suggests that tau pathology propagates trans-synaptically. However, the specific mechanisms occurring at the synapse remain poorly understood. This is partly attributed to the limitations of the models currently used to study this process. This research aimed to address these gaps by developing innovative in vitro and in vivo models with the aim of elucidating the processes driving tau release, endocytosis and accumulation at post-synaptic sites. A novel in vitro model was established using triangular microfluidic devices to mimic unidirectional synaptic connectivity. In this system, infecting an isolated population of neurons with the P301S-tau mutant led to the detection of tau-positive puncta and aggregates in synaptically connected neurons, suggestive of trans-synaptic tau transfer. Importantly, tau transfer was shown to depend on neuronal stimulation, supporting the notion that tau spreads in an activity-dependent manner. This model provides a platform to monitor and modulate tau propagation in vitro. A small panel of endocytic inhibitors were explored for their toxicity, activity and specificity in neuronal cultures which could be used in this model to elucidate the mechanisms of tau endocytosis at the post-synapse. Recent work has shown that mutant tau release is the superior colliculus was found to be dependent on the SNARE complex, particularly SNAP25. Using the same in vivo model of tau transfer, I demonstrate this SNAP25-dependent release of mutant tau is region specific. Further investigation into the trans-synaptic spread of tau found that mutant tau localised at the post-synapse and this process was inhibited by Botulinum toxin A (BoNT/A) further supporting SNAP25 dependency. Notably, mutant tau exhibited increased trans-synaptic spread compared to wild-type tau, highlighting its enhanced pathogenicity. These findings emphasise the role of activity and vesicle-mediated pathways, including SNAP25-dependent vesicle fusion, in tau propagation. Together, the developed models have the potential to advance our understanding of trans-synaptic tau transfer and provide valuable tools for investigating therapeutic strategies to disrupt pathological tau spread.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Modulating trans-synaptic tau transfer in vitro and in vivo |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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 Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10209450 |
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