Influence de Tau sur la physiologie rétinienne et la neuroplasticité visuelle chez la souris adulte

Le système visuel permet d’analyser et d’interpréter le monde qui nous entoure. L’intégration des stimuli visuels résulte de processus physiologiques et adaptatifs complexes. Ces processus adaptatifs font référence aux mécanismes de plasticité et à leur capacité à remodeler structurellement et fonctionnellement les circuits neuronaux. Fondamentale, la plasticité neuronale permet de s’adapter à son environnement. Les processus neurodéveloppementaux et adaptatifs consécutifs à une lésion dépendent en grande partie de mécanismes de plasticité, retrouvés dans l’ensemble du système nerveux central. De nombreux acteurs de la physiologie et de la plasticité neuro-visuelle ont été étudiés, souvent avec un objectif thérapeutique. Associée aux processus neurodégénératifs sous-jacents à de nombreuses neuropathologies, Tau, une protéine associée aux microtubules jouant un rôle dans le remodelage synaptique mais aussi dans la dynamique du cytosquelette, n’a jamais été étudiée dans la physiologie rétinienne et la plasticité visuelle. Notre hypothèse est que chez la souris adulte, Tau influence la physiologie rétinienne et les mécanismes de neuroplasticité visuelle. Notre premier objectif était d’étudier l’influence de la protéine Tau dans la physiologie rétinienne au cours du vieillissement. Nous avons comparé des souris exprimant la protéine Tau humaine dans un modèle de tauopathie modérée (hTau) à des souris déficientes pour la protéine Tau (Tau KO). L’influence de la protéine Tau dans la rétine est principalement étudiée d’un point de vue pathologique dans des modèles de tauopathies sévères associés à une surexpression de Tau mutée ou une augmentation pathologique de sa phosphorylation. Notre choix d’étudier les souris hTau reposait sur le fait que ces souris expriment la protéine Tau humaine non mutée et donc représentent un modèle plus proche de ce que l’on retrouve chez l’Homme. Cette étude a démontré que l’expression de la protéine Tau n’influençait pas la physiologie rétinienne au cours du vieillissement. Cette étude a suggéré également une toxicité neuronale différentielle de Tau entre la rétine et le cerveau dans un modèle modéré de tauopathie. Notre deuxième objectif était d’étudier l’influence de Tau dans la plasticité dépendante de l’expérience visuelle chez la souris adulte grâce au modèle de privation monoculaire. Tau est connue pour être impliquée dans les mécanismes de potentialisation à long terme. Cette seconde étude a permis de démontrer chez des souris sauvages (WT) que l’expression de Tau était modulée au cours du développement mais aussi au cours de l’induction de la plasticité visuelle en réponse à la privation monoculaire dans le cortex visuel. Grâce à l’étude du réflexe optocinétique permettant d’étudier l’acuité visuelle, en utilisant des souris Tau KO et des contrôles WT, nos résultats ont montré que Tau limite la plasticité visuelle chez l’adulte. L’analyse des cortex visuels a révélé un niveau d’expression de protéines associées à la plasticité plus élevé chez les souris Tau KO. Ces données ont permis de déterminer que la protéine Tau limite la plasticité visuelle chez la souris adulte. Notre troisième objectif était d’étudier le rôle de Tau dans la survie neuronale et la régénération axonale dans un modèle de lésion du nerf optique chez la souris adulte. La survie neuronale a été quantifiée sur rétines entières étalées et la régénération a été analysée par comptage des axones marqués grâce à un traceur antérograde injecté dans l’humeur vitrée. En utilisant des souris Tau KO et WT, nos analyses ont démontré que la protéine Tau n’influence ni la survie, ni la régénération axonale et ce, même lorsque la repousse axonale était favorisée par la libération soutenue de CNTF (ciliary neurotrophic factor), un facteur neurotrophique. Ces données ont mis en évidence que Tau n’influençait pas la survie neuronale et la régénération neuronale chez l’adulte. L’ensemble de nos résultats suggère donc que : 1/ Tau n’influence pas la physiologie rétinienne au cours du vieillissement et dans un modèle de tauopathie modérée, 2/ Tau limite la plasticité dépendante de l’expérience visuelle et 3/ Tau n’influence pas les mécanismes de survie neuronale et de régénération axonale du nerf optique. Pris ensemble, ces travaux mettent en évidence l’implication de Tau dans physiologie et les mécanismes de plasticité dans le système visuel. Ce nouveau rôle de Tau pourrait, à terme, mener au développement de nouvelles stratégies thérapeutiques dans le système visuel mais aussi plus généralement dans le système nerveux central lors d’altérations de la plasticité neuronale.The visual system allows us to analyze and interpret the world around us. The integration of visual stimuli results from complex physiological and adaptive processes. These adaptive processes refer to the mechanisms of plasticity and their ability to structurally and functionally reshape neural circuits. Basically, neuronal plasticity allows to adapt to the environment. The neurodevelopmental and adaptive processes consecutive to a lesion are largely dependent on mechanisms of plasticity found throughout the central nervous system. Many factors in physiology and neuro-visual plasticity have been studied, often with a therapeutic objective. Associated with the neurodegenerative processes underlying many neuropathologies, Tau, a microtubule-associated protein playing a role in synaptic remodeling but also in the dynamics of the cytoskeleton, has never been studied in retinal physiology and visual plasticity. Our hypothesis is that in adult mice, Tau influences retinal physiology and the mechanisms of visual neuroplasticity. Our first objective was to study the influence of the Tau protein in retinal physiology during aging. We compared mice expressing human Tau protein in a model of moderate tauopathy (hTau) to mice deficient in Tau protein (Tau KO). The influence of the Tau protein in the retina is most often studied from a pathological point of view in severe tauopathy models associated with an overexpression of mutated Tau or a pathological increase in its phosphorylation. Our choice to study hTau mice was based on the fact that these mice express the unmutated human Tau protein and therefore represent a model closer to what is found in humans. This study demonstrated that the Tau protein expression does not influence retinal physiology during aging. Also, this study suggested differential neuronal toxicity of Tau between the retina and the brain. Our second objective was to study the influence of Tau in visual experience-dependent plasticity in adult mice using the monocular deprivation model. Tau protein has been reported to be involved in long-term potentiation mechanisms. This study demonstrated in wild mice (WT) that the expression of Tau was modulated during development but also during the induction of visual plasticity in response to monocular deprivation in the visual cortex. Thanks to the study of the optokinetic reflex, using Tau KO mice and WT controls, our results showed that Tau limits visual plasticity in adults. Analysis of visual cortices revealed a higher level of expression of proteins associated with plasticity in Tau KO mice. These findings highlighted that Tau protein is an important factor in visual plasticity of the adult mice. Our third objective was to study the role of Tau in neuronal survival and axonal regeneration in a model of optic nerve damage in adult mice. Neuronal survival was quantified on whole flat-mount retinae and regeneration by counting stained regenerated axons using an anterograde tracer injected into the vitreous humor. Using Tau KO and WT mice, our analyzes demonstrated that the Tau protein does not influence survival or axonal regeneration significantly, even when axonal regrowth was improved by the sustained release of CNTF (ciliary neurotrophic factor), a neurotrophic factor. These data demonstrated that Tau does not influence retinal survival and neuronal regeneration in adults. All of our results therefore suggest that: 1 / Tau does not influence retinal physiology during aging and in a mild model of tauopathy, 2 / Tau limitates plasticity dependent on visual experience and 3 / Tau does not influence retinal survival and axonal regeneration mechanisms of the optic nerve. Overall, this work highlights Tau's involvement in physiological and neuronal plasticity mechanisms in the visual system. This new role of Tau could ultimately lead to the development of new therapeutic strategies in the visual system but also more generally in the central nervous system during alterations in neuronal plasticity

B cell-dependent EAE induces visual deficits in the mouse with similarities to human autoimmune demyelinating diseases.

BACKGROUND In the field of autoimmune demyelinating diseases, visual impairments have extensively been studied using the experimental autoimmune encephalomyelitis (EAE) mouse model, which is classically induced by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). However, this model does not involve B cells like its human analogs. New antigens have thus been developed to induce a B cell-dependent form of EAE that better mimics human diseases. METHODS The present study aimed to characterize the visual symptoms of EAE induced with such an antigen called bMOG. After the induction of EAE with bMOG in C57BL/6J mice, visual function changes were studied by electroretinography and optomotor acuity tests. Motor deficits were assessed in parallel with a standard clinical scoring method. Histological examinations and Western blot analyses allowed to follow retinal neuron survival, gliosis, microglia activation, opsin photopigment expression in photoreceptors and optic nerve demyelination. Disease effects on retinal gene expression were established by RNA sequencing. RESULTS We observed that bMOG EAE mice exhibited persistent loss of visual acuity, despite partial recovery of electroretinogram and motor functions. This loss was likely due to retinal inflammation, gliosis and synaptic impairments, as evidenced by histological and transcriptomic data. Further analysis suggests that the M-cone photoreceptor pathway was also affected. CONCLUSION Therefore, by documenting visual changes induced by bMOG and showing similarities to those seen in diseases such as multiple sclerosis and neuromyelitis optica, this study offers a new approach to test protective or restorative ophthalmic treatments

Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells

We present here a gene therapy approach aimed at preventing the formation of Ca2+-permeable amyloid pore oligomers that are considered as the most neurotoxic structures in both Alzheimer’s and Parkinson’s diseases. Our study is based on the design of a small peptide inhibitor (AmyP53) that combines the ganglioside recognition properties of the β-amyloid peptide (Aβ, Alzheimer) and α-synuclein (α-syn, Parkinson). As gangliosides mediate the initial binding step of these amyloid proteins to lipid rafts of the brain cell membranes, AmyP53 blocks, at the earliest step, the Ca2+ cascade that leads to neurodegeneration. Using a lentivirus vector, we genetically modified brain cells to express the therapeutic coding sequence of AmyP53 in a secreted form, rendering these cells totally resistant to oligomer formation by either Aβ or α-syn. This protection was specific, as control mCherry-transfected cells remained fully sensitive to these oligomers. AmyP53 was secreted at therapeutic concentrations in the supernatant of cultured cells, so that the therapy was effective for both transfected cells and their neighbors. This study is the first to demonstrate that a unique gene therapy approach aimed at preventing the formation of neurotoxic oligomers by targeting brain gangliosides may be considered for the treatment of two major neurodegenerative disorders, Alzheimer’s and Parkinson’s diseases

Pulpal and Periapical response after restoration of deep cavities in dogs' teeth with filtek silorane and filtek supreme xt systems.

Abstract OBJECTIVE: This study evaluated, histopathologically, the pulpal and periapical response to a silorane-based resin (Filtek Silorane) and a methacrylate-based nanoparticle resin (Filtek Supreme XT) in deep cavities in dogs, having zinc oxide and eugenol-based cement (ZOE) as a control. METHODS: The tooth/bone blocks were collected after 10 and 90 days and processed for microscopic analysis of the dentin, pulp, and periapical tissues using a score system. Data were analyzed statistically by Kruskal-Wallis and Dunn post-test (α=0.05). RESULTS: At 10 days, the pulp, connective tissue, and periodontal ligament showed normal characteristics. No resorption areas were observed. Both resins caused significantly less (p<0.05) periapical and pulpal inflammatory response than ZOE. At 90 days, for all materials, the connective pulp tissue was healthy and dense, with a normal blood vessel system. The apical and periapical region had normal structure and thickness. CONCLUSIONS: The use of the Filtek Silorane and the Filtek Supreme XT resins caused no adverse pulpal and periapical reactions after restoration of deep dentin cavities in vivo

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons

The implication of the microtubule-associated protein (MAP) Tau in the ocular manifestations of Alzheimer’s disease (AD) is elusive due to the lack of relevant animal model. However, signs of AD have been reported in the brain of transgenic mice expressing human Tau (hTau). To assess whether hTau is sufficient to induce AD pathogenesis in the retina as well, in the present study, we compared the retinal structure and function of KO mice deprived of Tau (mTKO) with those of transgenic mice expressing hTau. Our results revealed that hTau is particularly abundant in the inner nuclear layer (INL) cells of the retina. By electroretinogram (ERG) recording, light-induced retinal cell activation was not altered in hTau compared with mTKO littermates. Surprisingly, the ERG response mediated by cone photoreceptor stimulation was even stronger in hTau than in mTKO retinae. Immunofluorescent analysis of retinal sections allowed us to observe thicker inner retina in hTau than in mTKO eyes. By Western Blotting (WB), the upregulation of mTOR that was found in hTau mice may underlie retinal structure and function increases. Taken together, our results not only indicate that hTau expression is not toxic for retinal cells but they also suggest that it may play a positive role in visual physiology. The use of hTau may be envisaged to improve visual recovery in ocular diseases affecting the retinal function such as glaucoma or diabetic retinopathy

Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.

BACKGROUND Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD. METHODS We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). RESULTS The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aβ40 and Aβ42, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aβ load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. CONCLUSION Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females

Alteromonas Myovirus V22 Represents a New Genus of Marine Bacteriophages Requiring a Tail Fiber Chaperone for Host Recognition

Marine phages play a variety of critical roles in regulating the microbial composition of our oceans. Despite constituting the majority of genetic diversity within these environments, there are relatively few isolates with complete genome sequences or in-depth analyses of their host interaction mechanisms, such as characterization of their receptor binding proteins (RBPs). Here, we present the 92,760-bp genome of the Alteromonas-targeting phage V22. Genomic and morphological analyses identify V22 as a myovirus; however, due to a lack of sequence similarity to any other known myoviruses, we propose that V22 be classified as the type phage of a new Myoalterovirus genus within the Myoviridae family. V22 shows gene homology and synteny with two different subfamilies of phages infecting enterobacteria, specifically within the structural region of its genome. To improve our understanding of the V22 adsorption process, we identified putative RBPs (gp23, gp24, and gp26) and tested their ability to decorate the V22 propagation strain, Alteromonas mediterranea PT11, as recombinant green fluorescent protein (GFP)-tagged constructs. Only GFP-gp26 was capable of bacterial recognition and identified as the V22 RBP. Interestingly, production of functional GFP-gp26 required coexpression with the downstream protein gp27. GFP-gp26 could be expressed alone but was incapable of host recognition. By combining size-exclusion chromatography with fluorescence microscopy, we reveal how gp27 is not a component of the final RBP complex but instead is identified as a new type of phage-encoded intermolecular chaperone that is essential for maturation of the gp26 RBP.This work was supported by grants ‘VIREVO’ CGL2016‐76273‐P (MCI/AEI/FEDER, EU) (cofounded with FEDER funds) from the Spanish Ministerio de Ciencia e Innovación and ‘HIDRAS3’ PROMETEU/2019/009 from Generalitat Valenciana. R.G.-S. was supported by a predoctoral fellowship from the Valencian Consellería de Educació, Investigació, Cultura i Esport (ACIF/2016/050) and was also a beneficiary of the BEFPI 2019 fellowship for predoctoral stays from Generalitat Valenciana and The European Social Fund. F.R.-V. was a beneficiary of the 5top100 program of the Ministry for Science and Education of Russia

Association between Malnutrition Assessed by the Global Leadership Initiative on Malnutrition Criteria and Mortality in Older People: A Scoping Review.

peer reviewedThe Global Leadership Initiative on Malnutrition (GLIM) criteria were introduced in 2018 for the diagnosis of malnutrition in adults. This review was aimed at gathering the evidence about the association between malnutrition according to the GLIM criteria and mortality in older people, an emerging and clinically meaningful topic in the implementation of the GLIM criteria in geriatric healthcare settings. This scoping review considered meta-analyses, systematic reviews, cohort studies, and cross-sectional studies published in PubMed, Scopus, and the Cochrane Database for Systematic Reviews from the development of the GLIM criteria in 2018 to January 2023. Seventeen articles (15 cohort and 2 cross-sectional studies) were included. The association between GLIM criteria and mortality had been assessed in hospitalized (11 over the 17 articles) and community-dwelling older populations, and those in nursing homes. The review found a strong association between malnutrition according to GLIM criteria and mortality in hospitalized (1.2-fold to 7-fold higher mortality) and community-dwelling older people (1.6-fold to 4-fold higher mortality). These findings highlight the prognostic value of the GLIM criteria and support strategies towards the implementation of malnutrition evaluation according to the GLIM, in order to optimize comprehensive geriatric assessment and provide older people with the highest quality of nutritional care. Studies in nursing home populations were very scarce and may be urgently required

Fiber deprivation and microbiome-borne curli shift gut bacterial populations and accelerate disease in a mouse model of Parkinson's disease.

peer reviewedParkinson's disease (PD) is a neurological disorder characterized by motor dysfunction, dopaminergic neuron loss, and alpha-synuclein (αSyn) inclusions. Many PD risk factors are known, but those affecting disease progression are not. Lifestyle and microbial dysbiosis are candidates in this context. Diet-driven gut dysbiosis and reduced barrier function may increase exposure of enteric neurons to toxins. Here, we study whether fiber deprivation and exposure to bacterial curli, a protein cross-seeding with αSyn, individually or together, exacerbate disease in the enteric and central nervous systems of a transgenic PD mouse model. We analyze the gut microbiome, motor behavior, and gastrointestinal and brain pathologies. We find that diet and bacterial curli alter the microbiome and exacerbate motor performance, as well as intestinal and brain pathologies, but to different extents. Our results shed important insights on how diet and microbiome-borne insults modulate PD progression via the gut-brain axis and have implications for lifestyle management of PD.Deciphering the impact of exposures from the gut microbiome-derived molecular complex in human health and diseas