What did the team do and what did they find?
Using samples of human post-mortem brain tissue, Dr Durrant and the team first investigated how levels of phospho-tau 356 change as Alzheimer’s progresses, and found that the levels increased as the disease progressed. Using high resolution imaging, the researchers found phospho-tau 356 localised near synapses, suggesting it could directly damage these important connections between neurons.
Next, they looked at the impact of blocking the effects of NUAK-1 on slices taken from the brains of young mouse models, using an inhibitory drug. They found that the drug lowered the overall levels of tau in neurons and synapses. However, when they tested this in adult human brain slices, made from waste brain tissue generated during tumour removal surgery, the drug was more selective, only lowering phospho-tau 356.
What is the impact of these findings?
The study identifies phospho-tau 356 as a potential driver of Alzheimer’s, and shows that blocking NUAK-1 has differing effects in mouse and human brain cells. This may have important implications for the development of future anti-tau therapies and ensuring these translate effectively into treatments for human disease.
Dr Claire Durrant, Emerging Leader at the UK DRI at Edinburgh, said:
“This work demonstrates the importance of looking at enzymes that modify tau phosphorylation as potential therapeutic targets in Alzheimer’s disease. We also find interesting differences between the responses of mouse and human brain cells to the same drugs highlighting the importance of developing human models of disease. We hope our human brain slice model will help accelerate drug discovery for Alzheimer’s disease and result in greater success in the translation between the lab and the clinic.”
To find out more about Dr Claire Durrant’s research, visit her UK DRI profile. To stay up to date on the latest research news and institute updates, sign up to receive our monthly newsletter, ‘Inside Eye on UK DRI’.
Reference: Taylor, L.W., Simzer, E.M., Pimblett, C. et al. 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 (2024). https://doi.org/10.1007/s00401...
Article published: 4 January 2024
Banner image: Shutterstock/Juan Gaertner