Optimizing filter trap assay for the detection of aggregated alpha-synuclein in brain samples

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Expression and aggregation of α-synuclein and Tau in the enteric nervous system under inflammatory conditions

Les synucléinopathies et les tauopathies sont des maladies neurodégénératives caractérisées par une accumulation anormale et une agrégation des protéines α-synucléine et Tau, respectivement. La neuroinflammation joue un rôle central sur les fonctions physiologiques et l’agrégation de ces deux protéines. Parallèlement, au cours de la maladie de Parkinson, on retrouve les inclusions d’α-synucléine tout au long du tractus digestif et de nombreuses études ont mis en évidence la présence d’une inflammation intestinale chez les patients parkinsoniens. Dans ce contexte, nous avions émis l’hypothèse que l’inflammation intestinale pourrait altérer la régulation de ces deux protéines, mener à leur agrégation et possiblement leur propagation vers le SNC, et que le concept de synucléinopathie entérique pourrait s’étendre aux tauopathies. Ainsi, les objectifs de notre projet visaient à étudier le rôle de l’inflammation intestinale aiguë et chronique sur la régulation et l’agréation de l’α-synucléine et Tau. Nous avons montré, in vitro et in vivo, qu’une inflammation intestinale aiguë régulait à la baisse l’α-synucléine via une voie p38 dépendante. Inversement, dans des biopsies de patients Crohn, nous avons observé une régulation à la hausse de l’α-synucléine et de Tau, en l’absence de formes pathologiques. Cette régulation n’était pas liée à un mécanisme transcriptionnel mais serait due à une diminution de la dégradation de ces deux protéines via une voie NRF2/NDP52 dépendante. Ainsi, nos travaux suggèrent que l’inflammation intestinale altère l’expression de ces deux protéines clés et pourrait, sur le long terme, participer à leur pathogénicité.Synucleinopathies and tauopathies are neurodegenerative diseases characterized by abnormal accumulation and aggregation of the proteins α-synuclein and Tau, respectively. Neuroinflammation plays a central role in the physiological functions and aggregation of these two proteins. During Parkinson's disease, α-synuclein inclusions are found throughout the digestive tract and many studies have shown the presence of intestinal inflammation in Parkinson's patients. In this context, we hypothesized that intestinal inflammation could alter the regulation of these two proteins and that the concept of enteric synucleinopathy could extend to tauopathies. Thus, the objectives of our project aimed to study the role of acute and chronic intestinal inflammation on the regulation and aggregation of α-synuclein and Tau. We have shown, in vitro and in vivo, that acute intestinal inflammation downregulates α-synuclein via a p38 pathway, and that this regulation is specific to enteric neurons. On the other hand, in biopsies of Crohn’s disease patients, we have observed an upregulation of α-synuclein and Tau, in the absence of pathological forms. This regulation was not linked to a transcriptional mechanism but to a decrease in the degradation of these two proteins throughout a NRF2/NDP52 pathway. Therefore, our work suggests that intestinal inflammation dysregulates the expression of these two key proteins and could, in the long term, contribute to their pathogenicity

BDNF signaling and endothelial no production in rats subjected to physical training

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Opposite effects of hypertension and physical exercise on cerebrovascular BDNF levels

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Effect of short-term exercise training on brain-derived neurotrophic factor signaling in spontaneously hypertensive rats

International audienceObjective: Decreased brain-derived neurotrophic factor (BDNF) level has been reported in the hippocampus of hypertensive rats. The present study explored whether brain neurons and/or endothelial cells are targeted by hypertension with respect to BDNF expression and the potential of physical exercise to cope with hypertension.Methods: Physical exercise was induced in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. The hippocampus of sedentary and exercised rats (n = 6 for each group) were used for western blots to assess proBDNF, mature BDNF (mBDNF), tropomyosin-related kinase B (TrkB), P-TrkB(tyr816) (TrkB phosphorylated at tyrosine 816), synaptophysin, endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated at serine 1177 protein levels. BDNF and proBDNF localization in the hippocampus was studied in WKY rats, SHR and exercised SHR (n = 5 each). mBDNF and proBDNF protein levels were also assessed in hippocampal slices prepared from SHR (n = 10) that were incubated for 24 h with the nitric oxide (NO) donor glyceryl trinitrate. SBP was measured by the tail-cuff method.Results: Exercise modified blood pressure neither in SHR nor WKY. As compared with WKY rats, SHR displayed decreased levels of mBDNF, P-TrkB(tyr816), synaptophysin, eNOS and eNOS phosphorylated at serine 1177 but no change in proBDNF and TrkB levels. These effects coincided with low BDNF staining in both endothelial cells and neurons. Exercise improved the endothelium-derived NO system and the BDNF pathway in both strains. The NO donor increased mBDNF but decreased proBDNF levels.Conclusion: Our results revealed that endothelial and neuronal BDNF expressions were both impaired in hypertension and that physical exercise improved hippocampal mBDNF levels and signaling through blood pressure-independent mechanisms

Enzyme-based kinetic modelling of ASC–GSH cycle during tomato fruit development reveals the importance of reducing power and ROS availability

The ascorbate–glutathione (ASC–GSH) cycle is at the heart of redox metabolism, linking the major redox buffers with central metabolism through the processing of reactive oxygen species (ROS) and pyridine nucleotide metabolism. Tomato fruit development is underpinned by changes in redox buffer contents and their associated enzyme capacities, but interactions between them remain unclear. Based on quantitative data obtained for the core redox metabolism, we built an enzyme-based kinetic model to calculate redox metabolite concentrations with their corresponding fluxes and control coefficients. Dynamic and associated regulations of the ASC–GSH cycle throughout the whole fruit development were analysed and pointed to a sequential metabolic control of redox fluxes by ASC synthesis, NAD(P)H and ROS availability depending on the developmental phase. Furthermore, we highlighted that monodehydroascorbate reductase and the availability of reducing power were found to be the main regulators of the redox state of ASC and GSH during fruit growth under optimal conditions. Our kinetic modelling approach indicated that tomato fruit development displayed growth phase-dependent redox metabolism linked with central metabolism via pyridine nucleotides and H2O2 availability, while providing a new tool to the scientific community to investigate redox metabolism in fruits.The GLOMICAVE project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 95290

Factors associated with direct health care costs in schizophrenia: Results from the FACE-SZ French dataset

International audienceINTRODUCTION: There is a lack of data on health care consumption of patients suffering from schizophrenia, as well as on the related health care costs. Factors associated with health care costs have not been widely studied, whereas knowledge on this topic would allow identifying risk factors and delineating strategies to improve patients' health and follow-up, likely to also decrease health care costs. The aim of this study was to estimate the average direct health care cost of patients with schizophrenia in France and to identify the factors associated with this cost. METHODS: The study population included patients with schizophrenia enrolled in the FondaMental Advanced Centers of Expertise for Schizophrenia cohort. We accounted for the costs directly related to the treatment of schizophrenia. They included the costs of hospitalizations (full- and part-time), psychiatric ambulatory consultations and medications. We studied three categories of factors potentially associated with direct health care costs: demographic, socioeconomic and clinical characteristics. RESULTS: Three hundred and ninety five patients with schizophrenia were included. The mean (median) annual direct health care cost per patient amounted to \texteuro14,995 (\texteuro3,435). A lower level of functioning and being single were associated with a higher cost. A significant association between the expert center of inclusion and the direct health care cost of schizophrenia was also highlighted. CONCLUSION: Our results highlighted the significant cost of schizophrenia and suggest that improvement in patient care, based on well-validated targeted therapeutic interventions such as psycho-education and cognitive rehabilitation, could reduce worsening in symptom severity and therefore decrease health care costs

Enteric alpha-synuclein expression is increased in Crohn’s disease

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Etanercept improves endothelial function via pleiotropic effects in rat adjuvant-induced arthritis

International audienceObjectives. To determine the effect of etanercept on endothelial dysfunction and on traditional cardiovascular (CV) risk factors in the adjuvant- induced arthritis ( AIA) rat model.Methods. At the first signs of arthritis, etanercept (10 mg/kg/3 days, s.c.) or saline was administered for 3 weeks in AIA rats. Body weights and arthritis scores were monitored daily. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of nitric oxide synthase (NOS), cyclo-oxygenase (COX-2), arginase, endothelium-derived hyperpolarizing factor and superoxide anions (O(2)(-)A degrees) production. Aortic expression of endothelial nitic oxide synthase (eNOS), Ser1177-phospho-eNOS, COX-2, arginase-2, p22(phox) and p47(phox) was evaluated by western blotting analysis. Blood pressure, heart rate and blood levels of triglycerides, cholesterol and glucose were measured.Results. Etanercept significantly reduced arthritis score (P < 0.001). It improved Ach-induced relaxation (P < 0.05) as a result of increased NOS activity, decreased COX-2/arginase activities and decreased O(2)(-)A degrees production. These functional effects relied on increased eNOS expression and phosphorylation, and decreased COX-2, arginase-2 and p22(phox) expressions. No correlation was found between arthritis score and Ach-induced relaxation. The treatment did not change triglycerides, cholesterol and glucose levels, but significantly increased systolic blood pressure and heart rate (P < 0.05).Conclusion. Our data demonstrated that efficient dosage of etanercept on inflammatory symptoms improved endothelial function in AIA. This beneficial effect on endothelial function is disconnected from its impact on CV risk factors and relates to pleiotropic effects of etanercept on endothelial pathways. These results suggest that etanercept could be a good choice for patients with rheumatoid arthritis at high risk of CV events

Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy

Abstract Tau is normally a highly soluble phosphoprotein found predominantly in neurons. Six different isoforms of tau are expressed in the adult human CNS. Under pathological conditions, phosphorylated tau aggregates are a defining feature of neurodegenerative disorders called tauopathies. Recent findings have suggested a potential role of the gut-brain axis in CNS homeostasis, and therefore we set out to examine the isoform profile and phosphorylation state of tau in the enteric nervous system (ENS) under physiological conditions and in tauopathies. Surgical specimens of human colon from controls, Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) patients were analyzed by Western Blot and immunohistochemistry using a panel of anti-tau antibodies. We found that adult human ENS primarily expresses two tau isoforms, localized in the cell bodies and neuronal processes. We did not observe any difference in the enteric tau isoform profile and phosphorylation state between PSP, PD and control subjects. The htau mouse model of tauopathy also expressed two main isoforms of human tau in the ENS, and there were no apparent differences in ENS tau localization or phosphorylation between wild-type and htau mice. Tau in both human and mouse ENS was found to be phosphorylated but poorly susceptible to dephosphorylation with lambda phosphatase. To investigate ENS tau phosphorylation further, primary cultures from rat enteric neurons, which express four isoforms of tau, were pharmacologically manipulated to show that ENS tau phosphorylation state can be regulated, at least in vitro. Our study is the first to characterize tau in the rodent and human ENS. As a whole, our findings provide a basis to unravel the functions of tau in the ENS and to further investigate the possibility of pathological changes in enteric neuropathies and tauopathies