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

• DOI: 10.1007/s00401-023-02667-w
• Publication Date: 2024-01-04T10:02:37Z
• Authors: Lewis W. Taylor; Elizabeth M. Simzer; Claire Pimblett; Oscar T. T. Lacey...; Robert I. McGeachan; Soraya Meftah; Jamie L. Rose; Maxwell P. Spires...; Kristján Holt; James H. Catterson; Henner Koch; Imran Liaquat; Jonathan H. Clarke; John Skidmore; Colin Smith; Sam A. Booker; Paul M. Brennan; Tara L. Spires-Jones; Claire S. Durrant
• Keywords: Tauopathy; Hyperphosphorylation; Cyclin-dependent kinase 5; Tau protein

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