Caractérisation d'un modèle murin transgénique de la maladie d'Alzheimer et de vieillissement accéléré

Le vieillissement est un facteur clé dans la pathogenèse de la maladie d'Alzheimer (MA), forme la plus courante de démence chez la personne âgée. L'incidence de la MA est faible avant 65 ans ; celle-ci double ensuite tous les 5 à 6 ans pour dépasser 8 cas pour 100 années-personnes après 85 ans. Au cours des dernières décennies, plusieurs modèles transgéniques de la MA ont été conçus et caractérisés. Il a été observé que chez les souris qui surexprimaient les formes mutées de la protéine précurseur amyloïde-β (Aβ) humaine (hAPP) développaient des dépôts du peptide Aβ dans leur cerveau et des déficits de mémoire. Néanmoins, puisque le diagnostic de la MA repose sur la visualisation histologique de plaques Aβ et d’enchevêtrements neurofibrillaires de la protéine tau, le groupe du Dr LaFerla (Université de Californie, Irvine, É-U) a développé un modèle triple transgénique (3xTg-AD) exprimant trois transgènes : la protéine précurseur Aβ (APPSwe), préséniline-1 (PS1M146V) et tau (MAPTP301L). Cette lignée développe progressivement les pathologies Aβ et tau dans les régions cérébrales impliquées dans la MA, ainsi que des déficits de plasticité synaptique et de cognition. Toutefois, la souris 3xTg-AD ne développe pas de perte neuronale comme chez l’humain. Il est possible que les facteurs de vieillissement associés à la MA ne puissent pas s’exprimer pleinement en raison de leur courte espérance de vie. L’objectif de l’étude était de croiser la souris 3xTg-AD avec un modèle de sénescence accélérée, la souris SAMP8 (senescence-accelerated prone 8), afin de créer un modèle plus représentatif de la maladie humaine. Nos résultats montrent que les facteurs de sénescence liés au modèle SAMP8 ont accentué les déficits de mémoire et certains marqueurs neuropathologiques – en particulier la pathologie amyloïde – chez les souris 3xTg-AD femelles. Les données présentées mettent en évidence des interactions complexes entre les facteurs liés au génotype, au vieillissement et au sexe chez ce modèle.Aging is central to the pathogenesis of Alzheimer’s disease, the most common form of dementia during the elderly. The incidence of sporadic AD is low before 65 years old; it then doubles every 5 to 6 years to surpass 8 cases per 100 personyears after 85. To model AD, numerous transgenic mice have been produced and characterized in the last decades. It was found that mice overexpressing mutated forms of the human amyloid-β (Aβ) precursor protein (hAPP) develop Aβ deposits in their brain, along with quantifiable memory deficits. Since the diagnosis of AD is dependent upon the histological visualization of both Aβ plaques and tau-laden neurofibrillary tangles, Dr LaFerla’s group (University of California, Irvine, USA) has developed the triple-transgenic model (3xTg-AD) expressing three mutant transgenes: Aβ precursor protein (APPSwe), presenilin-1 (PS1M146V), and tauP301L. This mouse line progressively develops both Aβ and tau pathologies in AD-relevant brain regions as well as deficits in synaptic plasticity and cognitive performance. However, the 3xTg-AD mouse does not develop frank neuronal loss as found in AD brain. A likely simple explanation is that, within the lifespan of a mouse, AD-relevant aging factors do not have the time to be fully expressed. To that aim, we crossed senescence-accelerated prone 8 mice (SAMP8) with 3xTgAD mice to produce senescence-accelerated 3xTg-AD mice with the hope to generate a model closer to the human disease. Our results indicate that senescence acceleration amplifies memory deficits and several AD-related neuropathological features -particularly the amyloid pathology- in female 3xTg-AD mice. Overall, the present data suggest that the SAMP8/3xTg-AD mouse is a valuable model combining aging factors and AD neuropathology, but also evidence complex interactions between genetic backgrounds, aging- and sex-related factors

The Impact of Genetic Variability on the Relationship between Caffeine and Cardiometabolic Outcomes: A Systematic Review

The relationship between caffeine consumption and cardiometabolic health has been reported, albeit with heterogenous results. Discrepancies in study results may be due to inter-individual variability between study participants. This systematic review aimed to identify the impact of genetics on the relationship between caffeine consumption and cardiometabolic outcomes. Electronic databases (PubMed and EMBASE) were searched for studies published until July 2021. Selected studies were of both intervention and observational design and included: 1) analysis of at least one of the selected cardiometabolic outcomes (type 2 diabetes, glucose/insulin levels, cardiovascular disease, blood pressure or hypertension, blood lipids and catecholamines levels), 2) adults aged 18-65 and 3) genetic analysis of individuals consuming caffeine. Seventeen studies were included: four randomised controlled trials and an interventional and quasi-experimental study, six population-based prospective cohort studies, three cross-sectional studies and three case-control studies. CYP1A2 rs762551 and .ADORA rs5751876 were associated with glucose response when caffeine was consumed with carbohydrates. CYP1A2 rs762551 moderated the association between coffee intake and hypertension. Moreover, ADORA2A rs5751876 and the ADRA2B I variants moderated the associations between caffeine and blood pressure. Studies that investigated the effects of genetic variations on cardiovascular disease and caffeine consumption reported equivocal findings (CYP1A2) or warrant replication (COMT, ADORA, and TRIB1). Elucidating the extent to which these genes moderate the association between caffeine and cardiometabolic outcomes will enable caffeine consumption advice to be tailored to specific individuals to optimise health

Le tremblement essentiel : où en sommes-nous?

RésuméObjectifs : Discuter des modalités de traitement du tremblement essentiel. Source des données : Une revue de la documentation scientifique portant sur la pharmacothérapie du tremblement essentiel a été effectuée en recherchant des articles à partir de Pubmed entre 1975 et 2015 à l’aide des mots-clés suivants : adult, alprazolam, atenolol, benzodiazepines, botulinum toxin, clonazepam, deep brain stimulation, diazepam, essential tremor, gabapentin, lorazepam, metoprolol, nadolol, pediatrics, pharmacotherapy, phenobarbital, primidone, propranolol, sotalol, thalamotomy, topiramate. Les lignes directrices de l’American Academy of Neurology sur les traitements du tremblement essentiel révisées en 2011 ont également été consultées.Analyse des données : Le faible nombre d’essais cliniques à répartition aléatoire publiés et le nombre de patients inclus dans ces études sont deux problèmes fréquemment associés à la majorité des traitements étudiés pour le tremblement essentiel. De plus, les outils utilisés dans les essais cliniques pour évaluer l’efficacité des traitements à l’étude ne sont pas toujours bien décrits, ce qui rend l’interprétation des données complexe. Aucun essai clinique à répartition aléatoire n’a été publié sur le traitement du tremblement essentiel de l’enfant et de l’adolescent.Conclusion : Le tremblement essentiel est une maladie mal connue. Les traitements pharmacologiques ne permettent pas de guérir la maladie, mais vont plutôt atténuer les symptômes. Le propranolol et la primidone demeurent les agents pharmacologiques de première ligne pour l’adulte. Pour l’enfant et l’adolescent, la pharmacothérapie est rarement nécessaire, bien que le propranolol soit parfois utilisé en premier recours dans les cas plus sévères.AbstractObjectives: To discuss the treatment options for essential tremor.Data source: A review of the literature on the pharmacotherapy of essential tremor was conducted by searching PubMed from 2005 to 2015 for articles, using the following keywords: adult, alprazolam, atenolol, benzodiazepines, botulinum toxin, clonazepam, deep brain stimulation, diazepam, essential tremor, gabapentin, lorazepam, metoprolol, nadolol, pediatrics, pharmacotherapy, phenobarbital, primidone, propranolol, sotalol, thalamotomy, topiramate. The American Academy of Neurology’s 2011 revised guidelines on the treatments for essential tremor were also consulted.Data analysis: The small number of published randomized clinical trials and the number of patients included in these studies are two problems frequently encountered in the literature review for the treatment essential tremor. Furthermore, the tools used in clinical trials to evaluate their efficacy are not always clearly described, which makes interpreting the data a complex task. No randomized clinical trial has been published on the treatment of essential tremor in children and adolescents.Conclusion: Essential tremor is a poorly understood disorder. The pharmacological treatments are not a cure but rather alleviate the symptoms. Propranolol and primidone are the first-line pharmacological agents in adults. In children and adolescents, pharmacotherapy is seldom necessary. Propranolol is sometimes used as first-line therapy in more severe cases

Altered Protein Expression of Cardiac CYP2J and Hepatic CYP2C, CYP4A, and CYP4F in a Mouse Model of Type II Diabetes—A Link in the Onset and Development of Cardiovascular Disease?

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes in a tissue- and cell-specific manner to generate vasoactive products such as epoxyeicosatrienoic acids (EETs-cardioprotective) and hydroxyeicosatetraenoic acids (HETEs-cardiotoxic). Type II diabetes is a well-recognized risk factor for developing cardiovascular disease. A mouse model of Type II diabetes (C57BLKS/J-db/db) was used. After sacrifice, livers and hearts were collected, washed, and snap frozen. Total proteins were extracted. Western blots were performed to assess cardiac CYP2J and hepatic CYP2C, CYP4A, and CYP4F protein expression, respectively. Significant decreases in relative protein expression of cardiac CYP2J and hepatic CYP2C were observed in Type II diabetes animals compared to controls (CYP2J: 0.80 ± 0.03 vs. 1.05 ± 0.06, n = 20, p < 0.001); (CYP2C: 1.56 ± 0.17 vs. 2.21 ± 0.19, n = 19, p < 0.01). In contrast, significant increases in relative protein expression of both hepatic CYP4A and CYP4F were noted in Type II diabetes mice compared to controls (CYP4A: 1.06 ± 0.09 vs. 0.18 ± 0.01, n = 19, p < 0.001); (CYP4F: 2.53 ± 0.22 vs. 1.10 ± 0.07, n = 19, p < 0.001). These alterations induced by Type II diabetes in the endogenous pathway (CYP450) of arachidonic acid metabolism may increase the risk for cardiovascular disease by disrupting the fine equilibrium between cardioprotective (CYP2J/CYP2C-generated) and cardiotoxic (CYP4A/CYP4F-generated) metabolites of arachidonic acid