A5052800331- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Cholinesterase and Neurodegenerative Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Epigenetics and DNA Methylation
- Genetic Associations and Epidemiology
- S100 Proteins and Annexins
- Parkinson's Disease Mechanisms and Treatments
- Health, Environment, Cognitive Aging
- RNA regulation and disease
- Memory and Neural Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Bioinformatics and Genomic Networks
- Prion Diseases and Protein Misfolding
- Retinal Development and Disorders
- Genetic Syndromes and Imprinting
- Melanoma and MAPK Pathways
- Neurological and metabolic disorders
- Nerve Injury and Rehabilitation
- Spectroscopy Techniques in Biomedical and Chemical Research
- Dementia and Cognitive Impairment Research
- Folate and B Vitamins Research
- melanin and skin pigmentation
- CCD and CMOS Imaging Sensors
- Tissue Engineering and Regenerative Medicine
UK Dementia Research Institute
2022-2025
University of Edinburgh
2020-2025
Discovery Centre
2025
ORCID
2022
Colorado State University
2021
Roslin Institute
2020
In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain synapses are lost. Evidence from mouse models indicates that trans-synaptically pre- to postsynapses oligomeric is synaptotoxic, but data on synaptic in human scarce. Here we used sub-diffraction-limit microscopy study accumulation postmortem temporal occipital cortices of control donors. Oligomeric present postsynaptic terminals, even areas without abundant deposition. Furthermore, there a higher...
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...
Abstract Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta (Aβ) is implicated synaptic dysfunction loss. An important knowledge gap the lack of understanding how Aβ leads to synapse degeneration. In particular, there has been difficulty determining whether a receptor that binds mediates toxicity. While many candidates have observed model systems, their relevance human AD brain remains unknown. This part due methodological limitations...
In Alzheimer's disease, amyloid beta (Aβ) and tau pathology are thought to drive synapse loss. However, there is limited information on how endogenous levels of tau, Aβ other biomarkers relate patient characteristics, or manipulating physiological impacts synapses in living adult human brain. Using live brain slice cultures, we report that Aβ1-40 release vary with donor age region, respectively. Release such as KLK-6, NCAM-1, Neurogranin between while TDP-43 NCAM-1 impacted by sex....
Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation phenotypic study of circulating in relation to Methylome-wide association studies 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein after adjustment for multiple testing. These independent known genetic protein quantitative trait loci (pQTLs) common lifestyle effects. Phenome-wide...
Abstract In Alzheimer’s disease, it is theorised that amyloid beta (Aβ) and tau pathology contribute to synapse loss. However, there limited information on how endogenous levels of Aβ protein relate patient characteristics, or manipulating physiological impacts synapses, in living adult, human brain. Here, we employed live brain slice cultures as a translational tool assess release, pathology, response experimental manipulation. We found the 1-40 detected culture medium depend donor age,...
Abstract Feline cognitive dysfunction syndrome (CDS) is an age-related neurodegenerative disorder, comparable to dementia in people, characterised by behavioural changes such as increased vocalisation, altered social interactions, sleep-wake cycle, disorientation and house-soiling. Although the underlying mechanisms remain poorly understood, pathologies similar those observed Alzheimer’s disease (AD), have been identified brains of aged or CDS-affected cats, including brain atrophy, neuronal...
<title>Abstract</title> Feline diffuse iris melanoma (FDIM) is the most common primary ocular tumour in cats, with high metastatic potential. Greater intraocular invasion correlates increased mortality. No effective therapeutics exist for disease, partly due to a lack of known molecular targets associated aggressive behaviour. Here, we define transcriptomic landscape FDIM treatment-naïve cats using bulk RNA sequencing on laser capture microdissection and core biopsy specimens from...
Abstract Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. GABA B receptor (GABA R) signalling exerts powerful slow that controls synaptic, dendritic and neuronal activity. But, how Rs contribute to circuit-level over the lifespan of rodents humans poorly understood. In this study, we quantitatively determined functional contribution R pre- postsynaptic domains rat human cortical principal cells. We find differentially control...
Summary In Alzheimer’s disease (AD), fibrillar tau pathology accumulates and spreads through the brain synapses are lost. Evidence from mouse models indicates that trans-synaptically pre- to postsynapses oligomeric is synaptotoxic, but data on synaptic in human scarce. Here we used sub-diffraction-limit microscopy study accumulation post-mortem temporal occipital cortices of AD control donors. Oligomeric present both postsynaptic terminals even areas without abundant deposition. Further,...
Transitional cell carcinoma (TCC), also known as urothelial carcinoma, is the most common bladder cancer in humans and dogs. Approximately one-quarter of human TCCs are muscle-invasive associated with a high risk death from metastasis. Canine TCC (cTCC) tumours typically high-grade muscle-invasive. Shared similarities factors, histopathology, clinical presentation suggest that cTCC may serve model for assessment novel therapeutics inform therapies TCC. The goal this study was to characterize...
Abstract Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer’s disease, most common tauopathy, synapse loss is strongest pathological correlate of cognitive decline. Recently, PET imaging synaptic tracers revealed clinically relevant synapses primary tauopathies; however, molecular mechanisms leading to degeneration remain largely unknown. this study, we examined...
Summary Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. Much known about fast GABA currents, B receptor (GABA R) signalling exerts powerful slow that controls synaptic, dendritic and neuronal activity. However, little how Rs contribute to circuit-level over the lifespan of rodents humans. In this study, we quantitatively determine functional contribution R pre- postsynaptic domains rat human cortical principal cells (PC). We find...
Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, most common tauopathy, synapse loss is strongest pathological correlate of cognitive decline. Recently, Positron Emission Tomography (PET) imaging synaptic tracers revealed clinically relevant synapses primary tauopathies; however, molecular mechanisms leading to degeneration remain largely unknown....
Abstract In the neurodegenerative disease Progressive Supranuclear Palsy (PSP), tau pathology progresses through brain in a stereotypical spatiotemporal pattern, and where appears, synapses are lost. We tested hypothesis that spreads between regions PSP by moving from pre- to post-synapses. Sub-diffraction-limit microscopy of human post-mortem samples revealed oligomeric is present synaptic pairs PSP, with an 80-fold increased chance post-synapses containing when they oppose tau-containing...
A 4-month-old male entire domestic shorthair cat presented for sudden onset of right thoracic monoparesis following a fall; within 18 h, the clinical signs progressed to non-ambulatory hemiplegia with absent sensation in distal limb and left hemiparesis. MRI revealed changes consistent C6-C7 acute non-compressive nucleus pulposus extrusion suspected secondary C5-C7 spinal cord haemorrhage. Rehabilitation exercises were started immediately after diagnosis trauma. Sensation improved and, help...
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 been identified as potential mediator pathology, whereby NUAK1-mediated Ser356 prevents the degradation proteasome, further...
Abstract Background Maintaining synaptic health is essential for normal neurological function, yet neurodegenerative diseases like Alzheimer’s disease and Progressive Supranuclear Palsy (PSP) exhibit loss. In these conditions, loss precedes neuronal degeneration, the degree of correlates closely with severity clinical symptoms. Both Aβ, which accumulates in amyloid plaques AD, tau protein intracellularly tauopathies, including AD PSP, accumulate within terminals. model systems, accumulation...
Abstract Background Synapse loss represents the closest correlate of cognitive decline in Alzheimer’s Disease (AD). Standard microscopy, due to increased diffraction light with tissue depth, imposes a limit on axial resolution extending ∼ 700nm. Array tomography (AT) , developed by Micheva & Smith (2007), extends this via physical sectioning resin‐embedded into ribbons 70nm contiguous sections that are serially imaged and reconstructed 3D volumes; thus, allowing for nanometric synaptic...
Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with range neurological conditions. To provide insight into the molecular regulation S100β and its potential causal associations Alzheimer's disease, we carried out genome- epigenome-wide association studies (GWAS/EWAS) serum levels in older adults performed Mendelian randomisation disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) EWAS (N=722, were participants...