Gender-Specific Neuroimmunoendocrine Response to Treadmill Exercise in 3xTg-AD Mice

The 3xTg-AD mouse develops a progressive Alzheimer's disease- (AD-) like brain pathology that causes cognitive- and neuropsychiatric-like symptoms of dementia. Since its neuroimmunoendocrine axis is likewise impaired, this mouse is also useful for modelling complex age-related neurodegeneration. This study analyzed behavioral, physiological, neurochemical, pathological and immunoendocrine alterations in male and female 3xTg-AD mice and assayed the effects of a short therapy of forced physical exercise at the moderate pathology stage of 6 months of age. Gender effects were observed in most AD-related pathology and dysfunctions. Five weeks of treadmill training produced beneficial effects, such as the reduction of brain oxidative stress and GABA-A receptor dysfunction in males and improvement of sensorimotor function in females. In both sexes, exercise decreased the brain amyloid β 42/40 ratio levels. The results highlight the importance of analyzing experimental therapies in both mouse model genders in order to improve our understanding of the disease and develop more appropriate therapies

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Oxidative stress is a central target for physical exercise neuroprotection against pathological brain aging

Physical exercise is suggested for preventing or delaying senescence and Alzheimer’s disease (AD). We have examined its therapeutic value in the advanced stage of AD-like pathology in 3xTg-AD female mice through voluntary wheel running from 12 to 15 months of age. Mice submitted to exercise showed improved body fitness, immunorejuvenation, improvement of behavior and cognition, and reduced amyloid and tau pathology. Brain tissue analysis of aged 3xTg-AD mice showed high levels of oxidative damage. However, this damage was decreased by physical exercise through regulation of redox homeostasis. Network analyses showed that oxidative stress was a central event, which correlated with AD-like pathology and the AD-related behaviors of anxiety, apathy, and cognitive loss. This study corroborates the importance of redox mechanisms in the neuroprotective effect of physical exercise, and supports the theory of the crucial role of oxidative stress in the switch from normal brain aging to pathological aging and AD.Postprint (author’s final draft

Oxidative stress is a central target for physical exercise neuroprotection against pathological brain aging

Physical exercise is suggested for preventing or delaying senescence and Alzheimer’s disease (AD). We have examined its therapeutic value in the advanced stage of AD-like pathology in 3xTg-AD female mice through voluntary wheel running from 12 to 15 months of age. Mice submitted to exercise showed improved body fitness, immunorejuvenation, improvement of behavior and cognition, and reduced amyloid and tau pathology. Brain tissue analysis of aged 3xTg-AD mice showed high levels of oxidative damage. However, this damage was decreased by physical exercise through regulation of redox homeostasis. Network analyses showed that oxidative stress was a central event, which correlated with AD-like pathology and the AD-related behaviors of anxiety, apathy, and cognitive loss. This study corroborates the importance of redox mechanisms in the neuroprotective effect of physical exercise, and supports the theory of the crucial role of oxidative stress in the switch from normal brain aging to pathological aging and AD

INTERDISCIPLINARIETY IN HIGHER EDUCATION: A GUIDE PROPOSAL FOR ROLE PLAY DESIGN LA INTERDISCIPLINARIEDAD EN LA EDUCACIÓN SUPERIOR: PROPUESTA DE UNA GUÍA PARA EL DISEÑO DE JUEGOS DE ROL

<p align="justify">The aim of this article is to establish a teaching methodology that is integrated into the requests and necessities of the European Higher Education Area (EHEA), in which the undergraduate student must acquire all the professional competences guaranteeing the employability after his/her studies. We propose an interdisciplinary role play model based on the participation and collaboration among university teachers from different knowledge fields as well as undergraduate students from a great variety of the new Bachelor degrees. This model offers the teacher a useful guide for the design and the development of role play activities, whose aim is the acquisition and the implementation of general and specific competences of the new curricula. The use of an active methodology in our classrooms implies  the dinamization of the face to face teaching, since the game is the perfect element inviting the participation and motivation of the student. Thus, we fulfill one of our main objectives, that is, teaching the student to learn how to learn through the simulation of quasireal situations in the academic context.</p><br><p align="justify">Con este artículo pretendemos configurar una metodología docente que se integra en las demandas y necesidades del Espacio Europeo de Educación Superior (EEES), en el que el alumno debe adquirir competencias profesionales que le garanticen la empleabilidad tras la finalización de sus estudios. Se propone un modelo de juego de rol de carácter interdisciplinar basado en la participación y colaboración de profesores de diferentes áreas de conocimiento y de alumnos de distintos títulos de grado. Este modelo ofrece al docente una guía que facilita el diseño y desarrollo de juegos de rol, cuyo objetivo es la adquisición y puesta en práctica de competencias genéricas y específicas de los nuevos planes de estudio involucrados. El uso de una metodología activa en nuestras aulas implica la dinamización de la docencia presencial -porque el juego es un elemento que invita a la participación y motivación del estudiante-, cumpliéndose con ello uno de nuestros objetivos principales: enseñar al alumno a aprender a aprender, simulando situaciones cuasireales en el contexto académico.</p

LA INTERDISCIPLINARIEDAD EN LA EDUCACIÓN SUPERIOR: PROPUESTA DE UNA GUÍA PARA EL DISEÑO DE JUEGOS DE ROL

Con este artículo pretendemos configurar una metodología docente que se integra en las demandas y necesidades del Espacio Europeo de Educación Superior (EEES), en el que el alumno debe adquirir competencias profesionales que le garanticen la empleabilidad tras la finalización de sus estudios. Se propone un modelo de juego de rol de carácter interdisciplinar basado en la participación y colaboración de profesores de diferentes áreas de conocimiento y de alumnos de distintos títulos de grado. Este modelo ofrece al docente una guía que facilita el diseño y desarrollo de juegos de rol, cuyo objetivo es la adquisición y puesta en práctica de competencias genéricas y específicas de los nuevos planes de estudio involucrados. El uso de una metodología activa en nuestras aulas implica la dinamización de la docencia presencial -porque el juego es un elemento que invita a la participación y motivación del estudiante-, cumpliéndose con ello uno de nuestros objetivos principales: enseñar al alumno a aprender a aprender, simulando situaciones cuasireales en el contexto académico.</p

Teoría de la educación : educación y cultura en la sociedad de la información

Resumen basado en el de la publicaciónSe configura una metodología docente integrada en las demandas y necesidades del Espacio Europeo de Educación Superior (EEES), en el que el alumno debe adquirir competencias profesionales que le garanticen la inserción laboral tras la finalización de sus estudios. Se propone para ello un modelo de juego de rol de carácter interdisciplinar basado en la participación y colaboración de profesores de diferentes áreas de conocimiento y de alumnos de distintos títulos de grado. Este modelo ofrece al docente una guía que facilita el diseño y desarrollo de juegos de rol, cuyo objetivo es la adquisición y puesta en práctica de competencias genéricas y específicas de los nuevos planes de estudio involucrados. El uso de una metodología activa en las aulas implica la dinamización de la docencia presencial -porque el juego es un elemento que invita a la participación y motivación del estudiante-, cumpliéndose con ello uno de los objetivos principales: enseñar al alumno a aprender a aprender, simulando situaciones casi realales en el contexto académico.Castilla y LeónES

INTERDISCIPLINARIETY IN HIGHER EDUCATION: A GUIDE PROPOSAL FOR ROLE PLAY DESIGN

Con este artículo pretendemos configurar una metodología docente que se integra en las demandas y necesidades del Espacio Europeo de Educación Superior (EEES), en el que el alumno debe adquirir competencias profesionales que le garanticen la empleabilidad tras la finalización de sus estudios. Se propone un modelo de juego de rol de carácter interdisciplinar basado en la participación y colaboración de profesores de diferentes áreas de conocimiento y de alumnos de distintos títulos de grado. Este modelo ofrece al docente una guía que facilita el diseño y desarrollo de juegos de rol, cuyo objetivo es la adquisición y puesta en práctica de competencias genéricas y específicas de los nuevos planes de estudio involucrados. El uso de una metodología activa en nuestras aulas implica la dinamización de la docencia presencial -porque el juego es un elemento que invita a la participación y motivación del estudiante-, cumpliéndose con ello uno de nuestros objetivos principales: enseñar al alumno a aprender a aprender, simulando situaciones cuasireales en el contexto académico.The aim of this article is to establish a teaching methodology that is integrated into the requests and necessities of the European Higher Education Area (EHEA), in which the undergraduate student must acquire all the professional competences guaranteeing the employability after his/her studies. We propose an interdisciplinary role play model based on the participation and collaboration among university teachers from different knowledge fields as well as undergraduate students from a great variety of the new Bachelor degrees. This model offers the teacher a useful guide for the design and the development of role play activities, whose aim is the acquisition and the implementation of general and specific competences of the new curricula. The use of an active methodology in our classrooms implies the dinamization of the face to face teaching, since the game is the perfect element inviting the participation and motivation of the student. Thus, we fulfill one of our main objectives, that is, teaching the student to learn how to learn through the simulation of quasireal situations in the academic context