NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model.

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies

Métabolisme et pathologie Tau dans la maladie d'Alzheimer : une relation réciproque ?

Alzheimer's disease (AD) is a multifactorial disease that can be influenced by several genetic or environnemental factors, such as ApoEɛ4 allele, genetic polymorphisms and ageing and menopause, for instance. Since a decade epidemiological studies have pointed out the existence of a relationship between the metabolic status of individuals during their adult's life and an increased risk of developing AD at an advanced age. Indeed, type 2 diabetes doubles the risk to have AD. Mid-life overweight and obesity are also important risk factors for the development of AD. The work presented in this thesis aim at studying the impact of an obesity induced by a high-fat diet on physiopathological development of a transgenic mouse model reproducing AD-like Tau pathology, the THY-Tau22 mouse. This mouse overexpresses in the neurons a human Tau protein, mutated on two sites favoring its phosphorylation and aggregation and exhibits a progressive hippocampal Tau pathology in parallel with learning and memory impairment. This mouse model therefore constitutes an appropriate model to study the behavioral, anatomo-pathologic, biochemical and transcriptomic consequences of AD-like Tauopathy. Diet induced obesity and its metabolic disturbances in 7 months THY-Tau22 mice impaired learning and induced an aggravation of hippocampal Tau pathology. Interestingly, this pathological worsening occurred in parallel with healthy peripheral insulin sensitivity and activation of central insulin signaling. These data question the current dogma of the literature and suggest that deleterious consequences of obesity on Tau pathology could happen dissociated from peripheral and central insulin signaling. On the metabolic point of view, when fed high-fat, 7 months THY-Tau22 mice present, on the contrary of their littermate controls, a relative healthy glucose homeostasis. To control this phenotype we undertook the characterization of THY-Tau22 mice with a longitudinal study from 2 to 9 months. This characterization led us to underscore the leaner phenotype of THY-Tau22 compared to their WT counterparts, with increasing differences in metabolic parameters over age. In order to decipher if this metabolic feature is due to a gain of function induced by the neuronal overexpression of Tau we realized the same phenotyping on a Tau knock-out mouse (KO-Tau). The results indicate that, in contrary to THY-Tau22 mice, KO-Tau mice present a mirrored metabolic phenotype with higher body weight and impaired glucose homeostasis, suggesting a possible role for Tau in metabolic homeostasis. In conclusion, all the data presented in this thesis therefore suggest that obesity induces a worsening of AD-like Tau pathology that occurs dissociated from insulin resistance. Moreover, our study reveals the existence of a potential unpublished function of Tau protein whose action at central level could have peripheral metabolic consequences.La Maladie d’Alzheimer est une maladie multifactorielle dont l’apparition peut être influencée par divers facteurs génétiques ou environnementaux, tels l’allèle ApoEɛ4, différents polymorphismes ainsi que le vieillissement ou la ménopause, par exemple. Depuis une dizaine d’années des études épidémiologiques ont mis en évidence l’existence d’une relation entre le statut métabolique des individus durant leur vie adulte et l’augmentation du risque de développer la MA à un âge plus avancé. Les travaux présentés dans cette thèse visent à étudier l’impact d’un régime riche en graisse, permettant le développement d’une obésité, sur le développement physiopathologique d’un modèle transgénique mimant le versant Tau de la MA, la souris THY-Tau22. Cette souris surexprime dans les neurones du cerveau la protéine Tau humaine mutée en 2 sites favorisant sa phosphorylation et son agrégation et présente une pathologie Tau hippocampique évolutive qui s'exprime en parallèle d'altérations mnésiques. Ainsi, ce modèle murin constitue un modèle particulièrement adapté à l'étude des conséquences comportementales, anatomo-pathologiques, biochimiques et transcriptomiques de la tauopathie de la MA. L'induction d'une obésité et de ses conséquences métaboliques chez la souris THY-Tau22 de 7 mois a engendré une diminution des performances d'apprentissage accompagnée d'une aggravation de la pathologie Tau hippocampique. De façon intéressante, ces modifications pathologiques ont eu lieu en parallèle du maintien d'une bonne sensibilité à l'insuline périphérique et en présence d'une activation de la voie de signalisation du récepteur à l'insuline dans l'hippocampe. Ces données remettent en cause le dogme établit dans la littérature, et suggèrent que les conséquences délétères d'une obésité sur Tau dans la MA peuvent être dissociées d'une résistance à l'insuline périphérique et centrale. Sur le plan métabolique, lorsque nourries par un régime obésifiant, les souris THY-Tau22 de 7 mois présentent au contraire de leurs contrôles de portées wild-type une homéostasie glucidique peu détériorée. Afin de contrôler la véracité de ce phénotype nous avons entrepris la caractérisation métabolique de la lignée de souris THY-Tau22 via une étude longitudinale de 2 à 9 mois. Cette caractérisation a permis de mettre en évidence le caractère plus maigre de la souris THY-Tau22 comparé aux WT avec des différences de paramètres métaboliques qui s'accentuent au cours de la vie de la souris THY-Tau22. Afin de décrypter si cette particularité métabolique est le fruit du gain de fonction lié à la surexpression de la protéine Tau dans le cerveau de cette souris, un suivi longitudinal identique a été réalisé chez la souris Knock-out pour le gène Tau (KO-Tau). Les résultats indiquent que la souris KO-Tau présente un phénotype métabolique inverse à celui de la souris THY-Tau22, avec poids corporel augmenté et homéostasie glucidique altérée, suggérant que Tau puisse posséder un rôle dans l'homéostasie métabolique. En conclusion l’ensemble des résultats de cette thèse suggère par conséquent qu'une obésité provoque l'aggravation de la pathologie Tau de la MA, et ce, en l'absence d'une résistance à l'insuline. De plus, nous révélons l'existence d'une potentielle fonction inédite de la protéine Tau dont l'action au niveau central aurait des conséquences métaboliques périphériques

Metabolism and Tau pathology in Alzheime's disease : a reciprocal relationship ?

La Maladie d’Alzheimer est une maladie multifactorielle dont l’apparition peut être influencée par divers facteurs génétiques ou environnementaux, tels l’allèle ApoEɛ4, différents polymorphismes ainsi que le vieillissement ou la ménopause, par exemple. Depuis une dizaine d’années des études épidémiologiques ont mis en évidence l’existence d’une relation entre le statut métabolique des individus durant leur vie adulte et l’augmentation du risque de développer la MA à un âge plus avancé. Les travaux présentés dans cette thèse visent à étudier l’impact d’un régime riche en graisse, permettant le développement d’une obésité, sur le développement physiopathologique d’un modèle transgénique mimant le versant Tau de la MA, la souris THY-Tau22. Cette souris surexprime dans les neurones du cerveau la protéine Tau humaine mutée en 2 sites favorisant sa phosphorylation et son agrégation et présente une pathologie Tau hippocampique évolutive qui s'exprime en parallèle d'altérations mnésiques. Ainsi, ce modèle murin constitue un modèle particulièrement adapté à l'étude des conséquences comportementales, anatomo-pathologiques, biochimiques et transcriptomiques de la tauopathie de la MA. L'induction d'une obésité et de ses conséquences métaboliques chez la souris THY-Tau22 de 7 mois a engendré une diminution des performances d'apprentissage accompagnée d'une aggravation de la pathologie Tau hippocampique. De façon intéressante, ces modifications pathologiques ont eu lieu en parallèle du maintien d'une bonne sensibilité à l'insuline périphérique et en présence d'une activation de la voie de signalisation du récepteur à l'insuline dans l'hippocampe. Ces données remettent en cause le dogme établit dans la littérature, et suggèrent que les conséquences délétères d'une obésité sur Tau dans la MA peuvent être dissociées d'une résistance à l'insuline périphérique et centrale. Sur le plan métabolique, lorsque nourries par un régime obésifiant, les souris THY-Tau22 de 7 mois présentent au contraire de leurs contrôles de portées wild-type une homéostasie glucidique peu détériorée. Afin de contrôler la véracité de ce phénotype nous avons entrepris la caractérisation métabolique de la lignée de souris THY-Tau22 via une étude longitudinale de 2 à 9 mois. Cette caractérisation a permis de mettre en évidence le caractère plus maigre de la souris THY-Tau22 comparé aux WT avec des différences de paramètres métaboliques qui s'accentuent au cours de la vie de la souris THY-Tau22. Afin de décrypter si cette particularité métabolique est le fruit du gain de fonction lié à la surexpression de la protéine Tau dans le cerveau de cette souris, un suivi longitudinal identique a été réalisé chez la souris Knock-out pour le gène Tau (KO-Tau). Les résultats indiquent que la souris KO-Tau présente un phénotype métabolique inverse à celui de la souris THY-Tau22, avec poids corporel augmenté et homéostasie glucidique altérée, suggérant que Tau puisse posséder un rôle dans l'homéostasie métabolique. En conclusion l’ensemble des résultats de cette thèse suggère par conséquent qu'une obésité provoque l'aggravation de la pathologie Tau de la MA, et ce, en l'absence d'une résistance à l'insuline. De plus, nous révélons l'existence d'une potentielle fonction inédite de la protéine Tau dont l'action au niveau central aurait des conséquences métaboliques périphériques.Alzheimer's disease (AD) is a multifactorial disease that can be influenced by several genetic or environnemental factors, such as ApoEɛ4 allele, genetic polymorphisms and ageing and menopause, for instance. Since a decade epidemiological studies have pointed out the existence of a relationship between the metabolic status of individuals during their adult's life and an increased risk of developing AD at an advanced age. Indeed, type 2 diabetes doubles the risk to have AD. Mid-life overweight and obesity are also important risk factors for the development of AD. The work presented in this thesis aim at studying the impact of an obesity induced by a high-fat diet on physiopathological development of a transgenic mouse model reproducing AD-like Tau pathology, the THY-Tau22 mouse. This mouse overexpresses in the neurons a human Tau protein, mutated on two sites favoring its phosphorylation and aggregation and exhibits a progressive hippocampal Tau pathology in parallel with learning and memory impairment. This mouse model therefore constitutes an appropriate model to study the behavioral, anatomo-pathologic, biochemical and transcriptomic consequences of AD-like Tauopathy. Diet induced obesity and its metabolic disturbances in 7 months THY-Tau22 mice impaired learning and induced an aggravation of hippocampal Tau pathology. Interestingly, this pathological worsening occurred in parallel with healthy peripheral insulin sensitivity and activation of central insulin signaling. These data question the current dogma of the literature and suggest that deleterious consequences of obesity on Tau pathology could happen dissociated from peripheral and central insulin signaling. On the metabolic point of view, when fed high-fat, 7 months THY-Tau22 mice present, on the contrary of their littermate controls, a relative healthy glucose homeostasis. To control this phenotype we undertook the characterization of THY-Tau22 mice with a longitudinal study from 2 to 9 months. This characterization led us to underscore the leaner phenotype of THY-Tau22 compared to their WT counterparts, with increasing differences in metabolic parameters over age. In order to decipher if this metabolic feature is due to a gain of function induced by the neuronal overexpression of Tau we realized the same phenotyping on a Tau knock-out mouse (KO-Tau). The results indicate that, in contrary to THY-Tau22 mice, KO-Tau mice present a mirrored metabolic phenotype with higher body weight and impaired glucose homeostasis, suggesting a possible role for Tau in metabolic homeostasis. In conclusion, all the data presented in this thesis therefore suggest that obesity induces a worsening of AD-like Tau pathology that occurs dissociated from insulin resistance. Moreover, our study reveals the existence of a potential unpublished function of Tau protein whose action at central level could have peripheral metabolic consequences

Fmr1-Deficiency Impacts Body Composition, Skeleton, and Bone Microstructure in a Mouse Model of Fragile X Syndrome

International audienceFragile X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability, hyperactivity, and autism. FXS is due to the silencing of the X-linked FMR1 gene. Murine models of FXS, knock-out (KO) for the murine homolog Fmr1, have been generated, exhibiting CNS-related behavioral, and neuronal anomalies reminiscent of the human phenotypes. As a reflection of the almost ubiquitous expression of the FMR1 gene, FXS is also accompanied by physical abnormalities. This suggests that the FMR1-deficiency could impact skeletal ontogenesis. In the present study, we highlight that Fmr1-KO mice display changes in body composition with an increase in body weight, likely due to both increase of skeleton length and muscular mass along with reduced visceral adiposity. We also show that, while Fmr1-deficiency has no overt impact on cortical bone mineral density (BMD), cortical thickness was increased, and cortical eccentricity was decreased in the femurs from Fmr1-KO mice as compared to controls. Also, trabecular pore volume was reduced and trabecular thickness distribution was shifted toward higher ranges in Fmr1-KO femurs. Finally, we show that Fmr1-KO mice display increased physical activity. Although the precise molecular signaling mechanism that produces these skeletal and bone microstructure changes remains to be determined, our study warrants further investigation on the impact of FMR1-deficiency on whole-body composition, as well as skeletal and bone architecture

Materialism, Financial Motives and Gambling: Examination of an Unexplored Relationship

International audienceGambling has an inherent structural monetary component, and financial motive is one of the main motivations for gambling. Despite this, and contrary to other addictive behaviours that involve money such as compulsive buying, gambling has never been studied from a materialism perspective. The objective of the present study was to explore the links between materialism and gambling disorder (GD) and whether this relationship is mediated by financial motives for gambling. We compared 65 pathological gamblers (PGs) seeking treatment to 65 matched non-problem gamblers. The data collection included socio-demographics, gambling characteristics, the Materialism Values Scale, the Gambling Motives Questionnaire-Financial, and the Rosenberg Self-Esteem Scale. The statistical analysis included linear mixed models and Structural Equation Modelling. The level of materialism was significantly higher for the PGs, except for the Centrality dimension. Only one mediated effect was significant, and it concerned an indirect path from Happiness through financial motives. Moreover, Happiness explained most of the variance of the probability of becoming a PG. Contrary to compulsive buying, the PGs seemed to display materialism in a more experiential way that was centred on what possessions can induce secondarily rather than on the possessions themselves. The belief that material possessions are essential to achieving happiness may encourage the PG to gamble, thus contributing to both the development and maintenance of GD. We provided evidence that materialism is a key concept in the comprehension of GD and should be further considered when adapting care strategies

High-yield cellulose hydrolysis by HCl vapor: co-crystallization, deuterium accessibility and high-temperature thermal stability

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Interplay of Dietary Fatty Acids and Cholesterol Impacts Brain Mitochondria and Insulin Action

Overconsumption of high-fat and cholesterol-containing diets is detrimental for metabolism and mitochondrial function, causes inflammatory responses and impairs insulin action in peripheral tissues. Dietary fatty acids can enter the brain to mediate the nutritional status, but also to influence neuronal homeostasis. Yet, it is unclear whether cholesterol-containing high-fat diets (HFDs) with different combinations of fatty acids exert metabolic stress and impact mitochondrial function in the brain. To investigate whether cholesterol in combination with different fatty acids impacts neuronal metabolism and mitochondrial function, C57BL/6J mice received different cholesterol-containing diets with either high concentrations of long-chain saturated fatty acids or soybean oil-derived poly-unsaturated fatty acids. In addition, CLU183 neurons were stimulated with combinations of palmitate, linoleic acid and cholesterol to assess their effects on metabolic stress, mitochondrial function and insulin action. The dietary interventions resulted in a molecular signature of metabolic stress in the hypothalamus with decreased expression of occludin and subunits of mitochondrial electron chain complexes, elevated protein carbonylation, as well as c-Jun N-terminal kinase (JNK) activation. Palmitate caused mitochondrial dysfunction, oxidative stress, insulin and insulin-like growth factor-1 (IGF-1) resistance, while cholesterol and linoleic acid did not cause functional alterations. Finally, we defined insulin receptor as a novel negative regulator of metabolically stress-induced JNK activation

What Differs between Patients under Methadone and under Buprenorphine for Opioid Use Disorder (OUD) in Daily Clinical Practice in France? A Short Report

International audienceBackground: Opioid use disorder (OUD) is a complex condition that can require long-term treatment. Pharmacological therapy for OUD involves treatment with opioid agonists (OMT) tailored to individual profiles. The aim of our study in daily clinical practice was to compare the profiles of patients treated with methadone (MTD) and those using buprenorphine (BHD or BHD-naloxone-NX).Methods: A cross-sectional multicentre study explored the psychological, somatic and social profiles of patients with Opioid Use Disorder (OUD) following Opioid Maintenance Treatment (BHD, BHD/NX, or MTD). Descriptive and comparative analyses were performed Results: 257 patients were included, a majority were men using heroin. 68% (178) were on MTD, 32% (79) were on BHD. Patients with MTD were significantly more likely to report socio-affective damage, and more likely to be younger and not to report oral or sublingual use as the main route for heroin or non-medical opioidsConclusions: In daily clinical practice, regarding OUD damage, only socio-affective damage was significantly more prevalent among patients on MTD than among those on BHD in the multivariate model. Age and route of administration also differed, and our results could raise the issue of the type of OMT prescribed in case of non-medical use of prescribed opioids. These hypothesis should be confirmed in larger studie

How do people who use drugs receiving opioid medication therapy perceive their treatment ? A multicentre study.

BACKGROUND: The resurgence of heroin use and the misuse of pharmaceutical opioids are some of the reasons for a worldwide increase in opioid dependence. Opioid Medication Therapies (OMT) have amply demonstrated their efficacy. From a medical point of view, the main objectives of OMT concern medical and social outcomes, centred on risk reduction and the cessation of opioid use. But patient points of view can differ and few studies have explored opioid-dependent patient viewpoints on their OMT. This variable seems important to consider in a patient-centred approach. The aim of our study was to explore points of view of people who use drugs (PWUD) treated with OMT, in a large multicentre sample. METHOD: A cross-sectional multicentre study explored the points of view of PWUD with Opioid Use Disorder following OMT. Data regarding the patients' points of view were collected using a self-administered questionnaire developed by the scientific committee of the study. A descriptive analysis and an exploratory factor analysis were performed to explore the structure of items exploring patient viewpoints. RESULTS: 263 opioid dependent PWUD were included, a majority were men consuming heroin prior to being prescribed OMT. 68% were on methadone, 32% were on buprenorphine. Most PWUD identified a positive impact on their lives, with 92.8% agreeing or strongly agreeing that OMT had changed a lot of things in their lives. The exploratory factor analysis identified three factors: (F1) items related to points of views concerning the objectives and efficacy of OMT; (F2) items related to the legitimacy of OMT as a treatment compared to a drug, (F3) items related to experiences and relationships with OMT. CONCLUSION: Patient viewpoints on efficacy were correlated with the pharmacological benefits of OMT and with the associated psychosocial measures. The implications of OMT in relationships, such as the feeling of being judged, concerned a majority. Points of view were ambivalent concerning the role of OMT as a treatment or as a drug. Involving patient points of view in therapeutic strategies decisions could help enhance positive views among PWUD on OMT and help PWUD towards their recovery

Les technologies numériques et la transformation pédagogique

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