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p-tau Ser356 is associated with Alzheimer's disease pathology and is lowered in brain slice cultures using the NUAK inhibitor WZ4003.

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Simzer, Elizabeth M  ORCID logo
Lacey-Solymar, Oscar TT 
McGeachan, Robert I  ORCID logo


Tau hyperphosphorylation and aggregation is a common feature of many dementia-causing neurodegenerative diseases. Tau can be phosphorylated at up to 85 different sites, and there is increasing interest in whether tau phosphorylation at specific epitopes, by specific kinases, plays an important role in disease progression. The AMP-activated protein kinase (AMPK)-related enzyme NUAK1 has been identified as a potential mediator of tau pathology, whereby NUAK1-mediated phosphorylation of tau at Ser356 prevents the degradation of tau by the proteasome, further exacerbating tau hyperphosphorylation and accumulation. This study provides a detailed characterisation of the association of p-tau Ser356 with progression of Alzheimer's disease pathology, identifying a Braak stage-dependent increase in p-tau Ser356 protein levels and an almost ubiquitous presence in neurofibrillary tangles. We also demonstrate, using sub-diffraction-limit resolution array tomography imaging, that p-tau Ser356 co-localises with synapses in AD postmortem brain tissue, increasing evidence that this form of tau may play important roles in AD progression. To assess the potential impacts of pharmacological NUAK inhibition in an ex vivo system that retains multiple cell types and brain-relevant neuronal architecture, we treated postnatal mouse organotypic brain slice cultures from wildtype or APP/PS1 littermates with the commercially available NUAK1/2 inhibitor WZ4003. Whilst there were no genotype-specific effects, we found that WZ4003 results in a culture-phase-dependent loss of total tau and p-tau Ser356, which corresponds with a reduction in neuronal and synaptic proteins. By contrast, application of WZ4003 to live human brain slice cultures results in a specific lowering of p-tau Ser356, alongside increased neuronal tubulin protein. This work identifies differential responses of postnatal mouse organotypic brain slice cultures and adult human brain slice cultures to NUAK1 inhibition that will be important to consider in future work developing tau-targeting therapeutics for human disease.


Acknowledgements: We would like to thank the University of Edinburgh Bioresearch and Veterinary Services staff for their involvement in breeding and maintaining the mice used in this study. We thank the NRS BioResource and Tissue Governance unit and EMERGE Research Nurse team for their assistance in obtaining informed consent and surplus cortical tissue samples from NHS patients. We thank the MRC Edinburgh Brain Bank for providing human postmortem tissue. We thank Dr Faye McLeod and Dr Daniel Erskine for useful discussions on protocol development and optimisation for human brain slice cultures. Finally, we would like to thank patients and their families for their tissue donations.

Funder: James Dyson Foundation; doi:


Alzheimer’s disease, Human brain slice cultures, Mouse organotypic hippocampal slice cultures, NUAK1, Tau, p-tau Ser356, Adult, Humans, Animals, Mice, Alzheimer Disease, Brain, Anilides, Neurofibrillary Tangles, Protein Kinases, Repressor Proteins

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Acta Neuropathol

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Springer Science and Business Media LLC
Race Against Dementia (ARUK-RADF2019A-001)
Alzheimer's Society (581 (AS-PG-21-006))
UK Dementia Research Institute (UKDRI-Edin005)