Modelling strong lenses from wide-field ground-based observations in KiDS and GAMA

Despite the success of galaxy-scale strong gravitational lens studies with Hubble-quality imaging, a number of well-studied strong lenses remains small. As a result, robust comparisons of the lens models to theoretical predictions are difficult. This motivates our application of automated Bayesian lens modelling methods to observations from public data releases of overlapping large ground-based imaging and spectroscopic surveys: Kilo-Degree Survey (KiDS) and Galaxy and Mass Assembly (GAMA), respectively. We use the open-source lens modelling software PYAUTOLENS to perform our analysis. We demonstrate the feasibility of strong lens modelling with large-survey data at lower resolution as a complementary avenue to studies that utilize more time-consuming and expensive observations of individual lenses at higher resolution. We discuss advantages and challenges, with special consideration given to determining background source redshifts from single-aperture spectra and to disentangling foreground lens and background source light. High uncertainties in the best-fitting parameters for the models due to the limits of optical resolution in ground-based observatories and the small sample size can be improved with future study. We give broadly applicable recommendations for future efforts, and with proper application, this approach could yield measurements in the quantities needed for robust statistical inference

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

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.</p

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

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: http://dx.doi.org/10.13039/100014645AbstractTau 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.</jats:p