Genetically modified macrophages accelerate myelin repair

[EN] Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination. However, molecular targeting to MS lesions is a challenge. A clinically relevant paradigm for delivering Sema3F to demyelinating lesions could be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically modified hematopoietic stem cells (HSCs) as means of obtaining chimeric mice with circulating Sema3F-overexpressing monocytes. We demonstrated that Sema3F-transduced HSCs stimulate OPC migration in a neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion, which was conserved in middle-aged OPCs. While demyelinating lesions induced in mice with Sema3F-expressing blood cells showed no changes in inflammation and OPC survival, OPC recruitment was enhanced which accelerated the onset of remyelination. Our results provide a proof of concept that blood cells, particularly monocytes/macrophages, can be used to deliver pro-remyelinating agents "at the right time and place," suggesting novel means for remyelination-promoting strategies in MS.This work was supported by the French National Institute of Health and Medical Research (INSERM), French National Research Agency (ANR, project Stemimus ANR-12-BSV4-0002-02), the European Leukodystrophy Association (ELA, project 2016-004C5B), NeurATRIS, the program "Investissements d'avenir" (ANR-10-IAIHU-06), CIBERNED (CB06/0005/0076), and Gobierno Vasco (IT1203-19). VT was a recipient of the Spanish Ministry of Economy Young Investigator Grant (SAF2015-74332-JIN)

Ponyo sur la falaise : le testament mythopoétique de Hayao Miyazaki

Hayao Miyazaki est le maître incontesté de la fantasy animée depuis le milieu des années 1980 et la fondation du Studio Ghibli, qu’il a créé avec le réalisateur Isao Takahata et le producteur Toshio Suzuki. Primée à de nombreuses reprises à l’échelle internationale depuis une quinzaine d’années, son œuvre est assurément l’une des plus belles expressions du merveilleux moderne, que le mangaka envisage systématiquement au croisement de l’écriture et de la réécriture. Son art du conte se fonde en effet tout à la fois sur l’invention d’« autres mondes » imaginaires, sur l’intertextualité littéraire et sur la réinvention perpétuelle du folklore shintoïste et plus largement de la culture mythique universelle. Sorti sur les écrans nippons en 2009, le long-métrage initialement destiné à la jeunesse Ponyo sur la falaise serait, outre son ultime chef d’œuvre faërique, la synthèse de cette vision singulière de la création fictionnelle. D’où sa dimension testamentaire et métafictionnelle, que cette contribution se propose d’étudier

Le temps, le labyrinthe et le fantastique feint

Dans une conférence prononcée à Buenos Aires en 1985, un an avant sa mort, Borges définissait le temps en ces termes : Ce n’est pas la somme de tous nos hiers. C’est tous nos hiers, tous les hiers de tous les êtres conscients. Tout le passé, ce passé dont on ne sait quand il a commencé. Puis aussi tout le présent. Ce moment présent qui englobe toutes les villes, tous les mondes, tout l’espace entre les planètes. Puis, enfin l’avenir. L’avenir qui ne s’est pas encore réalisé mais qui, néanmoin..

Quand Lovecraft et Tolkien réinventent le signe lunaire

L’objet de cette réflexion est d’étudier comment Tolkien, pour la fantasy cosmique, et Lovecraft, pour le fantastique cosmique, ont pratiqué une même opération sur le signe lunaire dans le but de configurer au mieux leur « monde » imaginaire et leur « mythologie » artificielle respectifs. Mais avant, encore faudra-t-il décrire comment ils ont su transformer à la fois la « lune » que nous connaissons dans la réalité et celle que nous connaissons à travers les traditions magico-religieuses, aux..

Le temps recommencé (fictions du mythe et écritures fantastiques dans les oeuvres de Gautier, Kafka, Ray, Lovecraft, Tolkien et Borges)

L'appréhension moderne du temps se vide de ses attributs traditionnels : le sacré et la transcendance. Les anciennes réponses des oeuvres mythiques à l'angoisse de la fin et au fantasme de victoire sur l'entropie et sur la mort sont rejetées : le temps circulaire, l'immortalité et l'éternité. Mais ces phénomènologies révolues "ci-gîssent" dans le fantastique moderne, notamment chez Gautier, Kafka, Ray, Lovecraft, Tolkien et Borges. Sauf pour Tolkien, ces cadavres sacrés sont des moyens et non des fins grâce auxquels ils initient une priorité et une tradition esthétiques communes : faire valoir notre plaisir à imaginer l'existence réécrite autrement. Tous organisent ainsi un renouvellement du temps et, par là, une résistance de l'imaginaire face aux dérives de la pensée née de la nouvelle fascination pour la rationalité, la matérialité et la linéarité ; le tout en réécrivant les mythes puis leurs évolutions ultérieures, les métaphysiques.Modern perceptions of time are divested of their traditional attributes : sacredness and transcendance. Previous responses of mythical works of art to the anxiety of the end and to the fantasm of victory over entropy and death are rejected : circular time, immortality, eternity. But these outgrown phenomenologies are "subjacent" to modern fantastic genre, especially to Gautier, Kafka, Ray, Lovecraft, Tolkien and Borges. Except for Tolkien, these sacred corpses are means and not ends through which to initiate a common aesthetic priority and tradition : the value of our pleasure in imagining existence rewritten differently. Thus, they all organise a process of time renewal and, through this, a resistance of the imagination to the thought of their time, originating from the fascination for rationality, materiality and linearity ; all this by rewriting myths and their mataphysical outcomes.POITIERS-BU Droit Lettres (861942101) / SudocSudocFranceF

Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

Abstract Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer’s disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1- β, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-β plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD

Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.

International audienceAlzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing. The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies

Bioelectronic cell-based device provides a strategy for the treatment of the experimental model of multiple sclerosis

Wireless powered optogenetic cell-based implant provides a strategy to deliver subcutaneously therapeutic proteins. Immortalize Human Mesenchymal Stem Cells (hMSC-TERT) expressing the bacteriophytochrome diguanylate cyclase (DGCL) were validated for optogenetic controlled interferon-β delivery (Optoferon cells) in a bioelectronic cell-based implant. Optoferon cells transcriptomic profiling was used to elaborate an in-silico model of the recombinant interferon-β production. Wireless optoelectronic device integration was developed using additive manufacturing and injection molding. Implant cell-based optoelectronic interface manufacturing was established to integrate industrial flexible compact low-resistance screen-printed Near Field Communication (NFC) coil antenna. Optogenetic cell-based implant biocompatibility, and device performances were evaluated in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of multiple sclerosis.ISSN:0168-3659ISSN:1873-499