Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer's disease model

International audienceDeficits in synaptic structure and function are likely to underlie cognitive impairments in Alzheimer's disease. While synaptic deficits are commonly found in animal models of amyloidosis, it is unclear how amyloid pathology may impair synaptic functions. In some amyloid mouse models of Alzheimer's disease , however, synaptic deficits are preceded by hyperexcitability of glutamate synapses. In the amyloid transgenic mouse model TgCRND8, we therefore investigated whether early enhancement of gluta-matergic transmission was responsible for development of later synaptic deficits. Hippocampi from 1-month-old TgCRND8 mice revealed increased basal transmission and plasticity of glutamate synapses that was related to increased levels of tumor necrosis factor a (TNFa). Treating these 1-month-old mice for 4 weeks with the TNFa inhibitor XPro1595 prevented synaptic deficits otherwise apparent at the age of 6 months. In this mouse model at least, reversing the hyperexcitability of glutamate synapses via TNFa blockade before the onset of amyloid plaque formation prevented later synaptic deficits

Expression, pharmacology and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

Somatostatin (SRIF)-14 is recognized as an important mediator between the nervous and the immune system, although the functional role of its receptors (sst1-sst5) is poorly understood in humans. In our study, we demonstrate that human macrophages differentiated from peripheral blood mononuclear cell-derived monocytes express both sst1 and sst2 mRNAs. Both sst1 and sst2 are mostly localized at the cell surface and display active binding sites. In particular, sst1/sst2 activation results in a weak internalization of sst1 while the sst2 internalization appears more efficient. At the functional level, the activation of SRIF receptors by the multiligand analogues SOM230 and KE108, but not by SRIF-14 or cortistatin-14, reduces macrophage viability. Their effects are mimicked by the selective activation of sst1 and sst2 using CH-275 and SMS 201-995/L-779,976, respectively. Further, both sst1- and sst2-mediated effects are reversed by the sst1 antagonist SRA-880 or the sst2 antagonist CYN, respectively. CH-275, SMS 201-995 and L-779,976, but not SRIF-14, decrease both mRNA expression and secretion of the monocyte chemotactic protein-1. In addition, SRIF-14, CH-275, SMS 201-995 and L-779,976 decrease interleukine-8 secretion while they do not affect interleukine-8 mRNA expression. In contrast, SRIF-14 and sst1/sst2 agonists do not affect the secretion of matrix metalloproteinase-9. Collectively, our results suggest that the SRIF system, through sst1 and sst2, exerts mainly an immunosuppressive effect in human macrophages and may, therefore, represent a therapeutic window that can be exploited for the development of new strategies in pharmacological therapy of inflammation.L'articolo è disponibile sul sito dell'editore http://leukocytebiology.org/default.asp

Somatostatin agonist pasireotide promotes a physiological state resembling short-day acclimation in the photoperiodic male Siberian hamster (Phodopus sungorus)

The timing of growth in seasonal mammals is inextricably linked to food availability. This is exemplified in the Siberian hamster (Phodopus sungorus), which uses the annual cycle of photoperiod to optimally programme energy expenditure in anticipation of seasonal fluctuations in food resources. During the autumn, energy expenditure is progressively minimised by physiological adaptations, including a 30% reduction in body mass, comprising a reduction in both fat and lean tissues. However, the mechanistic basis of this adaptation is still unexplained. We hypothesised that growth hormone (GH) was a likely candidate to underpin these reversible changes in body mass. Administration of pasireotide, a long‐acting somatostatin receptor agonist developed for the treatment of acromegaly, to male hamsters under a long‐day (LD) photoperiod produced a body weight loss. This comprised a reduction in lean and fat mass, including kidneys, testes and brown adipose tissue, typically found in short‐day (SD) housed hamsters. Furthermore, when administered to hamsters switched from SD to LD, pasireotide retarded the body weight increase compared to vehicle‐treated hamsters. Pasireotide did not alter photoperiod‐mediated changes in hypothalamic energy balance gene expression but altered the expression of Srif mRNA expression in the periventricular nucleus and Ghrh mRNA expression in the arcuate nucleus consistent with a reduction in GH feedback and concurrent with reduced serum insulin‐like growth factor‐1. Conversely, GH treatment of SD hamsters increased body mass, which included increased mass of liver and kidneys. Together, these data indicate a role for the GH axis in the determination of seasonal body mass of the Siberian hamster

Redox homeostasis and age-related deficits in neuromuscular integrity and function

Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age-related muscleatrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributorto morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population(estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associatedwith neuromuscular ageing, will inevitably increase. Desp ite the importance of this ‘epidemic’ problem, the primarybiochemical and molecular mechanisms underlying age-related deficits in neuromuscular integrity and function have not beenfully determined. Skeleta l muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources,and age-associated oxidative damage has been suggested to be a major fac tor contributing to the initiation and progression ofmuscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, anddisruption of these events over time due to altered redox control has been proposed as an underlying mechanis m of ageing.The role of oxidants in ageing has been extensively examined in different model organisms that have undergone geneticmanipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function ofRONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redoxhomeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken inmurine models to examine the role of redox regulation in age-related muscle atrophy and weakness

Mécanismes de régulation par l'EGF [Epidermal Growth Factor] de la dynamique des cellules adénohypophysaires somatolactotropes

La dynamique d une population cellulaire dépend, très schématiquement, de l équilibre entre la division, la différenciation et la mort programmée. Le modèle des lignées cellulaires adénohypophysaires somatolactotropes (GH4C1) traitées à l EGF nous a permis d étudier les mécanismes de régulation de ces différents programmes génétiques. En effet, l EGF est capable d induire simultanément dans ces cellules un changement de profil sécrétoire, une mort cellulaire programmée et une inhibition de la division. La mort programmée atypique induite par l EGF possède un phénotype hétérogène et implique de nouveaux effecteurs comme la L-DNase II et Alix. L étude de l inhibition de la division cellulaire par l EGF nous a permis de montrer un contrôle transcriptionnel de l expression de la cycline D3 (une molécule clé du cycle cellulaire) par Pit-1 (un facteur de transcription impliqué dans la différenciation hypophysaire). Pit-1 participe donc à la régulation de la division des cellules GH4C1AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Régulations des fonctions mitochondriales dans la perspective de nouvelles pistes de traitement de la maladie d'Alzheimer

International audienceL’incidence de maladies métaboliques telles l’obésité, le diabète de type-2 et la maladie d’Alzheimer (MA), augmente partout dans le monde et devient un problème de santé publique préoccupant. Les mitochondries, au vu de leur rôle central dans la régulation du métabolisme, apparaissent comme un possible dénominateur commun de ces maladies. Or le fonctionnement des mitochondries repose sur la chaine respiratoire dont l’intégrité implique une protéine découverte pour son rôle dans la mort cellulaire par apoptose (AIF : Apoptosis Inducing Factor). Nous avons montré que dans le cortex frontal et temporal des patients décédés avec la MA, la diminution de la forme d’AIF protégeant l’intégrité de la chaine respiratoire, plutôt que l’induction de sa forme apoptotique, corrèle avec la maladie. AIF pourrait donc devenir une cible intéressante pour le développement de futures thérapies de maladies métaboliques, au-delà de la MA

Mort programmée induite par le NMDA dans l'hippocampe et lien avec la reprise du cycle cellulaire

La mort neuronale induite par l excès de glutamate (ou excitotoxicité) implique majoritairement les récepteurs de type -Methyl-D-Aspartate (RNMDA). Elle est associée à l induction paradoxale d un marqueur de la division cellulaire, la cycline D1, dont le rôle fonctionnel dans la mort neuronale reste peu connu. Pour aborder cette thématique, j ai utilisé comme modèle la culture primaire d hippocampes de rat (E18, 14jiv) traitée au NMDA. L expression de la cycline D1 augmente dès 2h de traitement et précède une mort massive de neurones, phénomène concomitant avec l augmentation de l incorporation de BrdU (un marqueur de la phase S du cycle cellulaire) et du Ki67 (un marqueur spécifique des cellules dans le cycle cellulaire). L excitotoxicité induite par le NMDA déclenche donc la reprise du cycle cellulaire sans division car les neurones meurent entre les phases G1 et S. J ai ensuite montré que la signalisation mise en jeu par le NMDA implique les RNMDA extra-synaptiques et l activation de JNK, une kinase de stress de la famille des MAP kinases. L activation de cette kinase joue un rôle crucial dans l induction de la mort neuronale par le NMDA car son inhibition pharmacologique bloque l induction de la cycline D1 et retarde la mort neuronale. Ces observations ont été confirmées par l inhibition de l expression de cycline D1 par des shRNA spécifiques. De façon importante, l activation de JNK s accompagne de l inhibition d une autre kinase de famille MAP, ERK. Pour comprendre les mécanismes à l origine du rôle de la cycline D1 dans l induction de la mort cellulaire, nous avons alors recherché un modèle dans lequel la transition division/ mort cellulaire peut être induite expérimentalement par l hormone leptine. Les résultats obtenus sur des cellules souches de zone sous-ventriculaire (ZSV) traitées par leptine montrent que, comme dans les cultures primaires d hippocampes, l induction de la cycline D1 via l activation d une kinase de famille MAP (respectivement ERK et JNK) précède la mort neuronale. Dans la ZSV, le changement de rôle de la cycline D1 (de la prolifération à l induction de la mort), semble associé à la régulation MAP-dépendante de l expression des protéines pro-apoptotiques de la famille Bcl2 qui diffère de celle observée en phase proliférative. L ensemble de ces résultats suggère donc que la cycline D1, utilisée par les cellules en phase proliférative en tant que médiateur de division a été détournée de son rôle premier chez les cellules en phase de différentiation terminale comme les neurones ou les précurseurs neuronaux de la ZSV traités par la leptine. Cette altération semble associée à la signalisation intra-cellulaire via les kinases de famille MAP, différentes selon l état de différenciation de cellules nerveuses.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Hippocampal oscillatory activity in Alzheimer's disease: toward the identification of early biomarkers?

International audienceAlzheimer's disease (AD) develops for a yet unknown period of time and can progress undiagnosed for years before its first clinical manifestation consisting of characteristic cognitive impairments. Current AD treatments offer only a small symptomatic benefit, likely because AD is diagnosed when the pathology is already well advanced, whereas treatments may be most efficient in the early phases of pathology. An accurate, early marker of AD is therefore needed to help diagnose AD earlier. It is now well documented that AD patients and animal models of AD exhibit reorganization of hippocampal and cortical networks. This reorganization is initiated by an early imbalance between excitation and inhibition, leading to altered network activity. The mechanisms underlying these changes are unknown but recent evidence suggests that either soluble amyloid-beta (Aß) or fibrillar forms of Aß are central to various network alterations observed in AD. However, recent evidence also suggests that Aβ over-production in animal models is not systematically linked to network over-excitation. We hypothesize here that early changes in the excitation-inhibition balance within the hippocampus occurs much earlier than currently believed and initially produces only slight changes in overall hippocampal activity. In this review, we introduce the concept according to which the subtle changes in theta and gamma rhythms might occur during the very first stages of AD and thus could be used as a possible predictor for the disease

Synaptic Activity and (Neuro)Inflammation in Alzheimer’s Disease: Could Exosomes be an Additional Link?

International audienceNanosized extracellular vesicles, known as exosomes, are produced by all cell types in mammalian organisms and have been recently involved in neurodegeneration. In the brain, both glia and neurons give rise to exosomes, which contribute to their intercellular communication. In addition, brain-derived exosomes have a remarkable property to cross the blood-brain-barrier bi-directionally. In this line, exosomes of central origin have been identified in peripheral circulation and already considered as putative blood biomarkers of neurodegenerative diseases, including Alzheimer’s disease (AD). Moreover, tentative use of exosomes as vehicle for the clearance of brain-born toxic proteins or, conversely, neuroprotective drug delivery, was also envisaged. However, little is known about the precise role of exosomes in the control and regulation of neuronal functions. Based on the presence of subunits of glutamate receptors in neuron-derived exosomes on one hand, and complement proteins in astrocyte-derived exosomes on the other hand, we hypothesize that exosomes may participate in the control of neuronal excitability via inflammatory-like mechanisms both at the central level and from the periphery. In this review, we will focus on AD and discuss the mechanisms by which exosomes of neuronal, glial, and/or peripheral origin could impact on neuronal excitability either directly or indirectly