"Understanding why synapses are damaged in Alzheimer’s disease provides the best hope for developing effective treatments. I hope that, one day, our research will help create a world free from the heartbreak of dementia." Claire Durrant
UK DRI Emerging Leader
Dr Claire Durrant is a Race Against Dementia (RAD) Dyson Fellow; supported by Sir Jackie Stewart’s pioneering dementia research charity and funded by the James Dyson Foundation. Prior to starting her RAD fellowship in September 2019, Dr Durrant completed her PhD and postdoctoral studies in the lab of Prof Michael Coleman at the University of Cambridge. She then moved to the University of Edinburgh in collaboration with her academic sponsor Prof Tara Spires-Jones, before becoming a UK DRI Emerging Leader in 2021. Dr Durrant specialises in using organotypic cultures and post-mortem human tissue to explore mechanisms of synapse loss in Alzheimer’s disease.
1. At a glance
In Alzheimer’s disease (AD), the loss of synapses, vital communication points between nerve cells, is thought to be the driving force behind memory loss. In AD, and related disorders such as frontotemporal dementia, tau, a normal protein found inside nerve cells, becomes “stickier”, clumping together to eventually form large aggregates called tangles. Aggregated tau can damage synapses but evidence suggests normal tau is also needed to keep synapses healthy. Tau clumping may therefore be a double-edged sword; turning tau toxic whilst simultaneously preventing its normal function.
Using thin slices of brain kept alive in culture dishes, Dr Durrant’s team are investigating the role of normal tau in keeping synapses healthy and how this changes in AD. These slice cultures, which contain the different cell types and synapses found in an intact brain, allow the team to easily test drugs and examine the sequence of changes in living tissue. This complements work in post-mortem brains, which provide a useful snapshot at the end-stages of the disease. This will aid understanding of what aspects of synapse damage in AD are caused by loss of normal tau function and enable researchers to design and refine therapies that provide the best outcome for synapses.
2. Scientific goals
Synapse loss is the best correlate of cognitive decline in Alzheimer’s disease (AD), so designing drugs that protect these structures is a key priority. Tau aggregation, likely driven by upstream changes in the amyloid pathway, is thought to be synaptotoxic and so lowering tau is often proposed as a therapeutic strategy. However, although constitutive tau knockout protects against aspects of AD pathology in various models, there is also mounting evidence that tau has important physiological roles at the synapse. This raises the possibility that tau loss-of-function may act alongside tau-toxicity to contribute to synapse damage in AD and related disorders. Tau-targeting therapeutics may therefore require careful optimisation to avoid induction, or worsening, of loss-of-function phenotypes.
Dr Durrant and her team are exploring the role of tau in synapse survival, determining whether tau loss of function plays a role in AD synaptic pathology, and testing potential mechanisms for therapeutic intervention.
Main objectives and research goals:
1. To test the hypothesis that reduction of endogenous tau protein results in glutamatergic synapse disruption and alterations in neuronal activity
2. To determine whether synaptic disruption in early AD can be partly attributed to loss of physiological tau function
3. To rescue synaptic function in AD models by restoring physiological tau or targeting downstream consequences of tau loss-of-function.
3. Team members
Dr James Catterson (Postdoctoral Researcher)
Dr Soraya Meftah (Postdoctoral Researcher)
Mr Lewis Taylor (PhD Student)
Dr Robert McGeachan (ECAT PhD Student- jointly with Spires-Jones lab)
Jamie Elliot (PhD student)
Danilo Negro (PhD student)
4. Collaborations
Within UK DRI:
- Prof Tara Spires-Jones, UK DRI at Edinburgh
Beyond UK DRI:
- Dr Paul Brennan, University of Edinburgh
- Dr Sam Booker, University of Edinburgh
5. Topics
Alzheimer’s disease, frontotemporal dementia, dementia, synapse, translational, human brain, organotypic cultures,
6. Techniques
Living human brain tissue, organotypic brain slice culture, mouse models, live imaging, western blots, ELISA, immunostaining, post-mortem human brain tissue,
7. Key publications
PREPRINT: James H. Catterson, Edmond Mouofo, Ines Lopez De Toledo Soler, Gillian Lean, Stella Dlamini, Phoebe Liddell, Yu-Chun Wang, Graham Voong, Patrik Verstreken, Tara L Spires-Jones, Claire S. Durrant* (2024) Drosophila appear resistant to trans-synaptic tau propagation. biorxiv: Doi: 10.1101/2024.03.11.584446
PREPRINT: Olivia Sheppard; Robert Humphrey; Claire S. Durrant; Michael P. Coleman (2024) Lowering glucose enables BACE1 activity and Aβ generation in mouse brain slice cultures biorxiv. Doi:10.1101/2024.03.12.584616
PREPRINT: Robert I. McGeachan, Soraya Meftah, Lewis W. Taylor, James H. Catterson, Danilo Negro, Jane Tulloch, Jamie L. Rose, Francesco Gobbo, Imran Liaquat, Tara L. Spires-Jones, Sam A. Booker, Paul M. Brennan, Claire S. Durrant* (2024) Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures biorxiv. Doi: 10.1101/2024.02.16.580676
PREPRINT: Robert I. McGeachan, Lois Keavey, Jamie L. Rose, Elizabeth M. Simzer, Ya Yin Chang, Maxwell P. Spires-Jones, Molie Gilmore, Natalia Ravingerova, Cristina Scutariu, Lewis W. Taylor, Declan King, Makis Tzioras, Jane Tulloch, Sam A. Booker, Imran Liaquat, Nicole Hindley-Pollock, Bethany Geary, Colin Smith, Paul M. Brennan, Claire S. Durrant*, Tara L Spires-Jones (2024) Evidence for trans-synaptic propagation of oligomeric tau in Progressive Supranuclear Palsy biorxiv. Doi: 10.1101/2022.09.20.22280086
Lewis W. Taylor, Elizabteh M. Simzwer, Claire Pimblett, Oscar T. T. Lacey-Solymar, Robert I. McGeachan, Soraya Meftah, Jamie L. Rose, Maxwell P. Spires-Jones, Kristjan Holt, James H. Catterson, Henner Koch, Imran Liaquat, Jonathan H. Clarke, John Skiddmore, Colin Smith, Sam A. Booker, Paul M. Brennan, Tara L. Spires-Jones, Claire S. Durrant* (2024) p-tau Ser356 is associated with Alzheimer’s disease pathology and is lowered in brain slice cultures using the NUAK inhibitor WZ4003 Acta Neuropathologica. Doi: 10.1007/s00401-023-02667-w
James H Catterson, Lucy Minkley, Salomé Aspe, Sebastian Judd-Mole, Sofia Moura, Miranda C Dyson, Arjunan Rajasingam, Nathaniel S Woodling, Magda L Atilano, Mumtaz Ahmad, Claire S Durrant, Tara L Spires-Jones, Linda Partridge (2023) Protein retention in the endoplasmic reticulum rescues Aβ toxicity in drosophila Neurobiology if Aging. Doi: 10.1016/j.neurobiolaging.2023.09.008
M Tzorias, RI McGeachan, CS Durrant, TL Spires-Jones (2022) Synaptic degeneration in Alzheimer disease Nature Reviews Neurology. Doi: https://doi.org/10.1038/s41582...
Marissa C. Vacher, Claire S. Durrant, Jamie Rose, Ailsa J. Hall, Tara L. Spires-Jones, Frank Gunn-Moore and Mark P. Dagleish (2022) Alzheimer’s like neuropathology in three species of oceanic dolphin European Journal of Neuroscience. Doi: https://doi.org/10.1111/ejn.15900
Kent SA, Spires-Jones TL, Durrant CS* (2020) The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics. Acta Neuropathologica. doi: 10.1007/s00401-020-02196-w
Durrant CS1* (2020) Preparation of Organotypic Hippocampal Slice Cultures for the Study of CNS Disease and Damage. Methods Mol Biol Clifton NJ 2143:133–144. doi: 10.1007/978-1-0716-0585-1_10
Durrant CS1, Ruscher K, Sheppard O, Coleman MP, Özen I (2020) Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling. Cell Death & Disease 11:1–15. doi: 10.1038/s41419-020-2288-4
Sheppard O, Coleman MP, Durrant CS* (2019) Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta. Journal of Neuroinflammation 16:106. doi: 10.1186/s12974-019-1490-8
Harwell CS1, Coleman MP (2016) Synaptophysin depletion and intraneuronal Aβ in organotypic hippocampal slice cultures from huAPP transgenic mice. Molecular Neurodegeneration 11:44. doi: 10.1186/s13024-016-0110-7
8. Lab website
Race Against Dementia Profile
Edinburgh Profile
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