Spires-Jones, Tara

Durrant, Claire

Sibley, Christopher

Mellanby, Richard

McGeachan, Robert

Wellcome Trust

2024-12-16T14:58:49Z

2024-12-16T14:58:49Z

2024-12-16

In the neurodegenerative disease, Progressive Supranuclear Palsy (PSP) tau pathology progresses through the brain in a stereotypical spatiotemporal pattern, and where tau pathology appears, synapses are lost. We tested the hypotheses that pathological tau and glia directly contribute to synapse loss and that tau pathology spreads between brain regions in PSP by moving from pre- to post-synapses. Subdiffraction-limit microscopy of human post-mortem PSP and control brain samples (n = 7) revealed that oligomeric tau is present in synaptic pairs in PSP, with an 80-fold increased chance of post-synapses containing tau when they oppose a taucontaining pre-synapse. In living human brain slice cultures (n = 5) PSP-derived oligomeric tau was taken up by post-synapses. Increased synaptic engulfment by astrocytes was observed in both post-mortem PSP brain and human brain slice cultures challenged with PSP-derived tau, whereas no increase in microglial synaptic engulfment was observed. Linear mixed-effect modelling was employed to analyse this data. An unbiased proteomics analysis of PSP total brain homogenate and biochemically isolated synapses (n = 10) supports the presence of neuroinflammation, astrocytic and synaptic changes in PSP brain, and highlights the need for further investigation into clusterin and syntaxin-6 as potential modulates of trans-synaptic tau propagation. These data indicate that tau pathology spreads via synapses in PSP and that astrocytes contribute to synapse loss. Targeting synaptic tau and astrocyte-mediated phagocytosis of synapses are promising targets for attenuating synaptic loss, tau pathology propagation and disease progression in PSP.

https://hdl.handle.net/1842/42902

http://dx.doi.org/10.7488/era/5455

en

The University of Edinburgh

McGeachan, R.I., Keavey, L., Rose, J.L., Simzer, E.M., Chang, Y.Y., Spires-Jones, M.P., Gilmore, M., Ravingerova, N., Scutariu, C., Taylor, L., King, D., Tzioras, M., Tulloch, J., Booker, S.A., Liaquat, I., Hindley-Pollock, N., Geary, B., Smith, C., Brennan, P.M., Durrant, C.S., Spires-Jones, T.L., 2024. Evidence for trans-synaptic propagation of oligomeric tau in Progressive Supranuclear Palsy. https://doi.org/10.1101/2022.09.20.22280086

Tzioras, M., McGeachan, R.I., Durrant, C.S., Spires-Jones, T.L., 2023. Synaptic degeneration in Alzheimer disease. Nat Rev Neurol 19, 19–38. https://doi.org/10.1038/s41582-022-00749-z

Colom-Cadena, M., Davies, C., Sirisi, S., Lee, J.-E., Simzer, E.M., Tzioras, M., Querol-Vilaseca, M., Sánchez-Aced, É., Chang, Y.Y., Holt, K., McGeachan, R.I., Rose, J., Tulloch, J., Wilkins, L., Smith, C., Andrian, T., Belbin, O., Pujals, S., Horrocks, M.H., Lleó, A., Spires-Jones, T.L., 2023. Synaptic oligomeric tau in Alzheimer’s disease — A potential culprit in the spread of tau pathology through the brain. Neuron 111, 2170-2183.e6. https://doi.org/10.1016/j.neuron.2023.04.020

Dando, O., McGeachan, R., McQueen, J., Baxter, P., Rockley, N., McAlister, H., Prasad, A., He, X., King, D., Rose, J., Jones, P.B., Tulloch, J., Chandran, S., Smith, C., Hardingham, G., Spires-Jones, T.L., 2024. Synaptic gene expression changes in frontotemporal dementia due to the MAPT 10+16 mutation. https://doi.org/10.1101/2024.04.09.24305501

McGeachan, R.I., Meftah, S., Taylor, L.W., Catterson, J.H., Negro, D., Tulloch, J., Rose, J.L., Gobbo, F., Liaquat, I., Spires-Jones, T.L., Booker, S.A., Brennan, P.M., Durrant, C.S., 2024. Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures. https://doi.org/10.1101/2024.02.16.580676

Taylor, L.W., Simzer, E.M., Pimblett, C., Lacey-Solymar, O.T.T., McGeachan, R.I., Meftah, S., Rose, J.L., Spires-Jones, M.P., Holt, K., Catterson, J.H., Koch, H., Liaquat, I., Clarke, J.H., Skidmore, J., Smith, C., Booker, S.A., Brennan, P.M., Spires-Jones, T.L., Durrant, C.S., 2024. p-tau Ser356 is associated with Alzheimer’s disease pathology and is lowered in brain slice cultures using the NUAK inhibitor WZ4003. Acta Neuropathol 147, 7. https://doi.org/10.1007/s00401-023-02667-w

Progressive Supranuclear Palsy

PSP

spatiotemporal pattern

tau pathology

oligomeric tau

astrocytes

synaptic tau

phagocytosis of synapses

Investigating the mechanisms of synapse loss and tau propagation in progressive supranuclear palsy

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy