Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Altres ajuts: Fundació "la Caixa" ID 100010434; PIF UABAcord transformatiu CRUE-CSICLeigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurodegeneration and neuroinflammation, thereby leading to deteriorating neurological symptoms, including motor deficits, breathing alterations, and eventually, death of the animal. However, despite the magnitude of neuroinflammation associated with brain lesions, the role of neuroinflammatory pathways and their main cellular components have not been addressed directly as relevant players in the disease pathology. Here, we investigate the role of microglial cells, the main immune cells of the CNS, in Leigh-like syndrome pathology, by pharmacologically depleting them using the colony-stimulating factor 1 receptor antagonist PLX3397. Microglial depletion extended lifespan and delayed motor symptoms in Ndufs4 KO mice, likely by preventing neuronal loss. Next, we investigated the role of the major cytokine interleukin-6 (IL-6) in the disease progression. IL-6 deficiency partially rescued breathing abnormalities and modulated gliosis but did not extend the lifespan or rescue motor decline in Ndufs4 KO mice. The present results show that microglial accumulation is pathogenic, in a process independent of IL-6, and hints toward a contributing role of neuroinflammation in the disease of Ndufs4 KO mice and potentially in patients with Leigh syndrome

Astrocytic IL-6 Influences the Clinical Symptoms of EAE in Mice

Interleukin-6 (IL-6) is a multifunctional cytokine that not only plays major roles in the immune system, but also serves as a coordinator between the nervous and endocrine systems. IL-6 is produced in multiple cell types in the CNS, and in turn, many cells respond to it. It is therefore important to ascertain which cell type is the key responder to IL-6 during both physiological and pathological conditions. In order to test the role of astrocytic IL-6 in neuroinflammation, we studied an extensively-used animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), in mice with an IL-6 deficiency in astrocytes (Ast-IL-6 KO). Results indicate that lack of astrocytic IL-6 did not cause major changes in EAE symptomatology. However, a delay in the onset of clinical signs was observed in Ast-IL-6 KO females, with fewer inflammatory infiltrates and decreased demyelination and some alterations in gliosis and vasogenesis, compared to floxed mice. These results suggest that astrocyte-secreted IL-6 has some roles in EAE pathogenesis, at least in females

Interleukin-6-elicited chronic neuroinflammation may decrease survival but is not sufficient to drive disease progression in a mouse model of Leigh syndrome

BackgroundMitochondrial diseases (MDs) are genetic disorders characterized by dysfunctions in mitochondria. Clinical data suggest that additional factors, beyond genetics, contribute to the onset and progression of this group of diseases, but these influencing factors remain largely unknown. Mounting evidence indicates that immune dysregulation or distress could play a role. Clinical observations have described the co-incidence of infection and the onset of the disease as well as the worsening of symptoms following infection. These findings highlight the complex interactions between MDs and immunity and underscore the need to better understand their underlying relationships.ResultsWe used Ndufs4 KO mice, a well-established mouse model of Leigh syndrome (one of the most relevant MDs), to test whether chronic induction of a neuroinflammatory state in the central nervous system before the development of neurological symptoms would affect both the onset and progression of the disease in Ndufs4 KO mice. To this aim, we took advantage of the GFAP-IL6 mouse, which overexpresses interleukin-6 (IL-6) in astrocytes and produces chronic glial reactivity, by generating a mouse line with IL-6 overexpression and NDUFS4 deficiency. IL-6 overexpression aggravated the mortality of female Ndufs4 KO mice but did not alter the main motor and respiratory phenotypes measured in any sex. Interestingly, an abnormal region-dependent microglial response to IL-6 overexpression was observed in Ndufs4 KO mice compared to controls.ConclusionOverall, our data indicate that chronic neuroinflammation may worsen the disease in Ndufs4 KO female mice, but not in males, and uncovers an abnormal microglial response due to OXPHOS dysfunction, which may have implications for our understanding of the effect of OXPHOS dysfunction in microglia

A new mouse model to study restoration of interleukin-6 (IL-6) expression in a Cre-dependent manner : microglial IL-6 regulation of experimental autoimmune encephalomyelitis

Altres ajuts: "La Marató TV3" 20142210Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6. To give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss of Il6 expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglial Il6 expression in IL6-DIO-KO mice through breeding to Cx3cr1 -CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10-16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG) 7 weeks after TAM treatment to induce EAE. Clinical symptoms and demyelination, CD3 infiltration, and gliosis in the spinal cord were evaluated. IL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglial Il6 was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology. IL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE

Investigació: L’atenció a l’alumnat amb discapacitat a la URV. Una guia docent

En els moments actuals, l’accés i la integració de les persones amb discapacitat als estudis universitaris es pot considerar com un fenomen en ple procés d’expansió. A principis dels anys noranta la presència d’estudiants amb discapacitat als campus universitaris era un fet anecdòtic i avui en dia és ja una sòlida realitat. El reconeixement social dels principis d’igualtat d’oportunitats, normalització, i els canvis realitzats també a nivell legislatiu amb la creació de normatives sobre l’educació de les persones amb discapacitat, ha contribuït a aquest increment

Rúbrica d'autoavaluació de competències i habilitats personals i prosocials

Les competències i habilitats personals i prosocials dels estudiants són centrals per a la formació docent i sovint són complexes d'avaluar en el marc de la formació universitària. Amb la intenció de promoure aquestes competències i la seva avaluació, l'Equip de Recerca Sumant Compromís Educatiu ha elaborat una rubríca d'avaluació per evidenciar el desenvolupament de les competències personals i prosocials per facilitar la reflexió d'alumnes, professors i mestres. Tant per a l'autoconeixement i l'autoavaluació dels estudiants en el seu procés i progrés d'aprenentatge (abans, durant i després de fer l'estada de pràctiques), com també per al seu seguiment i l'avaluació dels mestres i tutors de la universitat. La rúbrica ha estat utilitzada i valorada per estudiants d'infantil i primària així com també per mestres d'escola bressol, parvulari i primària durant el projecte. Tot i que les competències i habilitats personals i prosocials que avalua aquesta rúbrica són les indicades al Programa dels Graus de Mestres d'Educació Infantil i de Primària, es defineixen com a competències transversals per a les diverses professions dedicades a l'educació, el benestar i a la Salut; per tant, es pot fer servir també en altres àmbits

Rúbrica de autoevaluación de competencias y habilidades personales y prosociales

Las competencias y habilidades personales y prosociales de los estudiantes son centrales para la formación docente y a menudo son complejas de evaluar en el marco de la formación universitaria. Con la intención de promover estas competencias y su evaluación, el Equip de Recerca Sumant Compromís Educatiu ha elaborado una rúbrica de evaluación para evidenciar el desarrollo de las competencias personales y prosociales para facilitar la reflexión de alumnos, profesores y maestros. Tanto para el autoconocimiento y la autoevaluación de los estudiantes en su proceso y progreso de aprendizaje (antes, durante y después de hacer la estancia de prácticas), así como para su seguimiento y la evaluación de los maestros y tutores de la universidad. La rúbrica ha sido utilizada y valorada por estudiantes de infantil y primaria así como también para maestros de jardín de infancia, parvulario y primaria durante el proyecto. Aunque las competencias y habilidades personales y prosociales que evalúa esta rúbrica son las indicadas en el Programa de los Grados de Maestros de Educación Infantil y de Primaria, se definen como competencias transversales para las diversas profesiones dedicadas a la educación, el bienestar ya la Salud; por tanto, se puede usar también en otros ámbitos

Copper Modulation as a Therapy for Alzheimer's Disease?

The role of metals in the pathophysiology of Alzheimer's disease (AD) has gained considerable support in recent years, with both in vitro and in vivo data demonstrating that a mis-metabolism of metal ions, such as copper and zinc, may affect various cellular cascades that ultimately leads to the development and/or potentiation of AD. In this paper, we will provide an overview of the preclinical and clinical literature that specifically relates to attempts to affect the AD cascade by the modulation of brain copper levels. We will also detail our own novel animal data, where we treated APP/PS1 (7-8 months old) mice with either high copper (20 ppm in the drinking water), high cholesterol (2% supplement in the food) or a combination of both and then assessed β-amyloid (Aβ) burden (soluble and insoluble Aβ), APP levels and behavioural performance in the Morris water maze. These data support an interaction between copper/cholesterol and both Aβ and APP and further highlight the potential role of metal ion dyshomeostasis in AD

IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer's Disease

Altres ajuts: Fundació La Marató de TV3 (20142210)Alzheimer's disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD

Influence of transgenic metallothionein-1 on gliosis, CA1 neuronal loss, and brain metal levels of the Tg2576 mouse model of Alzheimer's disease

The mouse model of Alzheimer's disease (AD), Tg2576 mice (APP), has provided valuable information, such as the role of the metallothionein (MT) family in their behavioral and amyloidosis phenotypes. In this study, we further characterize the role of MT-1 by crossing Mt1-overexpressing mice with Tg2576 mice (APPTgMT). In 14-month-old mice, MT-1(/2) protein levels were dramatically increased by Mt1 overexpression throughout the cortex (Cx), which showed a prominent caudal-rostral gradient, and the hippocampus (HC). There was a trend for MT-1(/2) immunostaining to be increased in the areas surrounding the amyloid plaques in control male mice but not in Mt1-overexpressing mice. Gliosis was elicited by the amyloid plaques, but the effects of Mt1 overexpression were modest. However, in hippocampal western blots the microglial marker Iba-1 was increased in old male APPTgMT mice compared to APP-wild type (APPWT) mice, and the opposite was observed in young mice. Hippocampal CA1 neuronal loss was observed in Tg2576 mice, but was unaffected by Mt1 overexpression. Aging increased Zn and Cu levels differently depending on brain area, sex, and genotype. Thus, the effects of Mt1 overexpression on the phenotype of Tg2576 mice here studied are modest