Study uncovers potential driver of Alzheimer’s disease progression

A study led by Dr Claire Durrant (UK DRI at Edinburgh) reveals fresh insight into the role of the protein tau in the progression of Alzheimer’s disease. The research, published in the journal Acta Neuropathologica, could have important implications for the development of future therapeutics.

What was the challenge?

Misfolded tau protein accumulates in clumps or ‘tangles’ in the brains of people affected by Alzheimer’s and other neurodegenerative diseases. The protein can be chemically altered or ‘phosphorylated’ by enzymes, and it is not yet well understood whether this plays a role in driving disease progression.

One such enzyme, known as NUAK-1, has been shown to alter tau in a way that prevents it from being cleared away, and allows tangles to accumulate. The team examined a particular form of phosphorylated tau created by NUAK-1, called phospho-tau 356, and its association with the progression of Alzheimer’s disease.

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