The Prostaglandin E2 Receptor Subtype 3E and its involvement in tauopathies

Neuroinflammation is becoming increasingly recognised as key to the pathogenesis of Alzheimer’s disease and tauopthies. Epidemiological studies report a delay in the onset of Alzheimer’s in subjects using nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit enzymes in the cyclooxygenase-2 (COX-2) pathway which play a key role in synthesising prostaglandin E2 (PGE2) from arachidonic acid. PGE2 has been implicated in preclinical stages of Alzheimer’s disease, where elevated levels of PGE2 in the cerebrospinal fluid can be found, as well as aberrant amyloid processing in experimental models of disease. PGE2 signals via 4 E-prostanoid (EP) receptors, EP1-EP4, all G-protein coupled receptors (GPCR). The EP3 receptor, the most abundant PGE2 receptor in the brain, is unique in that it is alternatively spliced giving rise to species specific isoforms. One of the EP3 receptor isoforms, EP3Re, is human specific and an incidental finding within a project to investigate its distribution in brain, suggested that it could be associated with tau tangles. The aim of this project was to further investigate the unknown distribution of EP3Re in human brain, to determine its signalling mechanism and explore whether any meaningful interaction between EP3Re, tau and its pathology exists. We use immunohistochemistry, proximity ligation assays and electron microscopy to map out the distribution of EP3Re in the human brain and explore the interaction between EP3Re and tau. We also use gene reporter and second messenger assays to characterise EP3Re signalling and what role if any this may be playing in tauopathies. We show that EP3Re is expressed throughout the brain, with strong expression in brain stem nuclei, and signals predominantly through a Gi coupling pathway. Moreover, using a combination of human tissue, primary cell lines and neurons derived from induced pluripotent stem cells, we show that EP3Re appears to be associated with tau neurofibrillary tangles in disease. We also show, using the EP3 agonist sulprostone, that signalling through the receptor increases tau phosphorylation in our cellular systems. Further work will be required to fully clarify the specificity of the interaction and understand the mechanism behind this and if targeting inflammatory EP3Re signalling has the potential to affect tau pathology in disease.John Van Geest studentship; Alzheimer's Research UK (ARUK

Validation of the new pathology staging system for progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder associated with neuroglial accumulation of 4-repeat tau protein [2]. Kovacs et al. [1] have recently proposed a new semi-quantitative six-stage system to categorise the severity of PSP pathology. Importantly, the system reduces reliance on regions with high risk of concomitant pathology and focusses on cell type specific tau-pathology.Cambridge Centre for Parkinson-plus (RG95450), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre

In vivo 18F-flortaucipir PET does not accurately support the staging of progressive supranuclear palsy

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods: N=42 patients with probable PSP and N=39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the staging system for PSP pathology, the combination of absent/present values across all regions was evaluated to assign each participant to in vivo stages. Analysis of variance was applied to analyse differences among means of disease severity between stages. In vivo staging was compared with post-mortem staging in N=9 patients who also had post-mortem confirmation of the diagnosis and stage. Results: Stage assignment was estimable in 41 patients: N=10 patients were classified in stage I/II, N=26 in stage III/IV, N=5 in stage V/VI, while N=1 was not classifiable. An explorative sub-staging identified N=2 patients in stage I, N=8 in stage II, N=9 in stage III, N=17 in stage IV and N=5 in stage V. However, the nominal 18F-flortaucipir derived stage was not associated with clinical severity and was not indicative of pathology staging at post-mortem. Conclusion: 18F-flortaucipir PET in vivo does not correspond to neuropathological staging in PSP. This analytic approach, seeking to mirror in vivo the neuropathology staging with PET-to-autopsy correlational analyses might enable in vivo staging with next-generation PET tracers for tau, but further evidence and comparison with post-mortem data are needed.This study was co-funded by the Cambridge University Centre for Parkinson-Plus (RG95450); the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014), including their financial support for the Cambridge Brain Bank; the PSP Association (“MAPT-PSP” award); the Alzheimer’s Research UK East-Network pump priming grant; the Wellcome trust (220258); the Medical Research Council (MR/P01271X/1; G1100464); the Association of British Neurologists, Patrick Berthoud Charitable Trust (RG99368); Alzheimer’s Society (443 AS JF 18017); the Evelyn Trust (RG84654), and RCUK/UKRI (via a Research Innovation Fellowship awarded by the Medical Research Council to CHWG - MR/R007446/1); the Guarantors of Brain (G101149). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care

Accurate digital quantification of tau pathology in progressive supranuclear palsy

Acknowledgements: We would like to thank the people who kindly donated their brains for this study, and their families. The Cambridge Bank is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312).Funder: Progressive Supranuclear Palsy Association; doi: http://dx.doi.org/10.13039/501100008177Funder: Lundbeck Foundation; doi: http://dx.doi.org/10.13039/501100003554AbstractThe development of novel treatments for Progressive Supranuclear Palsy (PSP) is hindered by a knowledge gap of the impact of neurodegenerative neuropathology on brain structure and function. The current standard practice for measuring postmortem tau histology is semi-quantitative assessment, which is prone to inter-rater variability, time-consuming and difficult to scale. We developed and optimized a tau aggregate type-specific quantification pipeline for cortical and subcortical regions, in human brain donors with PSP. We quantified 4 tau objects (‘neurofibrillary tangles’, ‘coiled bodies’, ‘tufted astrocytes’, and ‘tau fragments’) using a probabilistic random forest machine learning classifier. The tau pipeline achieved high classification performance (F1-score &gt; 0.90), comparable to neuropathologist inter-rater reliability in the held-out test set. Using 240 AT8 slides from 32 postmortem brains, the tau burden was correlated against the PSP pathology staging scheme using Spearman’s rank correlation. We assessed whether clinical severity (PSP rating scale, PSPRS) score reflects neuropathological severity inferred from PSP stage and tau burden using Bayesian linear mixed regression. Tufted astrocyte density in cortical regions and coiled body density in subcortical regions showed the highest correlation to PSP stage (r = 0.62 and r = 0.38, respectively). Using traditional manual staging, only PSP patients in stage 6, not earlier stages, had significantly higher clinical severity than stage 2. Cortical tau density and neurofibrillary tangle density in subcortical regions correlated with clinical severity. Overall, our data indicate the potential for highly accurate digital tau aggregate type-specific quantification for neurodegenerative tauopathies; and the importance of studying tau aggregate type-specific burden in different brain regions as opposed to overall tau, to gain insights into the pathogenesis and progression of tauopathies.</jats:p

Multisystem pathology in McLeod syndrome

We present comprehensive characterisation of clinical, neuropathological and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioural change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum Creatinine Kinase (CK) was first noted in his thirties but investigations including muscle biopsy at that time were inconclusive. Brain MRI showed white matter volume loss, atrophic basal ganglia and chronic small vessel ischaemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis found a hemizygous pathogenic variant in the XK gene c.895C>T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. He died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen and mild Alzheimer’s pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When suspecting a clinical diagnosis, candidate genes should be interrogated, rather than solely relying on exome panels

Multisystem pathology in McLeod syndrome.

Funder: Medical Research CouncilFunder: National Institute for Health and Care Research; doi: http://dx.doi.org/10.13039/501100000272Funder: Wellcome Trust; doi: http://dx.doi.org/10.13039/100010269We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).

Funder: National Institute for Health and Care Research; Id: http://dx.doi.org/10.13039/501100000272Funder: NHS England; Id: http://dx.doi.org/10.13039/100012360Funder: The Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269Funder: Cancer Research UK; Id: http://dx.doi.org/10.13039/501100000289Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100007155Funder: St Baldrick's Foundation International Scholars ProgramFunder: Kai Slockers Pediatric Cancer Research FundFunder: Stand Up To Cancer Maverick AwardFunder: Hold'em for Life Foundatio