GSK3 and tau: Two convergence points in Alzheimer's disease

Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer's disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filaments, and GSK3 activity contributes both to amyloid-β production and amyloid-β-mediated neuronal death. Thus, mice generated in our laboratory with conditional overexpression of GSK3 in forebrain neurons (Tet/GSK3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis, as well as spatial learning deficit. In this review, we describe recent contributions of our group showing that transgene shutdown in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK3 inhibitors for AD therapeutics. In addition, we have combined transgenic mice overexpressing the enzyme GSK3β with transgenic mice expressing tau with a triple FTDP-17 mutation that develop prefibrillar tau-aggregates. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Further, it is possible to partially reverse tau pathology in advanced stages of the disease, although the presence of already assembled neurofibrillary tangle-like structures cannot be reversed. © 2013 The authors and IOS Press. All rights reserved.Peer Reviewe

El descubrimiento de las proteínas fluorescentes y su utilidad en la investigación biomédica (Premio Nobel de Química 2008)

Nobel Prize on Chemistry, 2008 has been granted to Osamu Shimomura, Martin Chalfie and Roger Y. Tsien for the discovery of the green flourescent protein (GFP) and for the development of tools based on that for its application in biotechnology and biomedical research.El premio Nobel de Química 2008 ha sido otorgado a los científicos Osamu Shimomura, Martin Chalfie y Roger Y. Tsien por el descubrimiento de la proteína verde fluorescente (GFP, por sus iniciales en inglés) y por el desarrollo de herramientas derivadas de ésta para su aplicación en biotecnología y en investigación biomédica

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

© 2014, Springer Science+Business Media New York. The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the up-regulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase-4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy.Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de Salud Carlos III) and by grants fromMinisterio de Ciencia (MICINN, MINECO) SAF2009-08233 and SAF2012-34177 and Fundación Ramón Areces to JJL. Grant 2009/SGR00853 from the Generalitat de Catalunya (Autonomous Government of Catalonia) and grants BFU2010-19119/BFI to CA, SAF2011-23631 to AC, and SAF2012-39852-C02-01 to MP from the Spanish Ministerio de Ciencia (MICINN, MINECO) also supported the study. Grant 0177594 from CONACYT (Mexico)Peer Reviewe

Psychometric properties of the intention to be physically active scale in primary education

Los objetivos de este estudio fueron los siguientes: en primer lugar, conocer las características psicométricas de la adaptación de la escala Medida de la Intencionalidad de ser Físicamente Activo para su aplicación a una población de Educación Primaria y, en segundo lugar, comprobar dicha medida en esa misma etapa educativa. Se seleccionó a 657 alumnos. El trabajo de investigación se dividió en dos partes. En la primera, se adaptó el instrumento; para ello, se consultó a 12 jueces expertos para obtener la validez de contenido y a 24 niños para obtener la validez de comprensión. En la segunda etapa, se administró el instrumento y se obtuvieron los datos. En cuanto al primer objetivo, los expertos y los niños sugirieron la adaptación y clarificación de cuatro ítems. El análisis factorial exploratorio reveló que todos los ítems se agruparon en un factor (varianza explicada = 50,88%) y el análisis factorial confirmatorio resultó aceptable (χ2 / g. l. = 4,83; CFI = ,93; GFI = ,91; RMSEA = ,06). El instrumento tuvo una alta consistencia interna (α= ,80), así como fiabilidad temporal (ICC = ,79). En cuanto al segundo objetivo, los participantes declararon una intención futura de práctica deportiva alta (3,94). La variable edad influyó en la predicción de la intencionalidad futura de práctica deportiva (B = ,529; ET = ,192; p = ,006). La intencionalidad de práctica futura de los participantes de 11 a 12 años fue mayor que la de los que tenían entre 9 y 10 años (F = 8,684; g. l. = 1; p = 0,003; η2 = 0,013). En conclusión, este estudio presenta un instrumento válido, fiable y sencillo para conocer la intención futura que los alumnos de Primaria tienen de ser físicamente activos. Los participantes, en especial los de más edad, mostraron una alta intencionalidad de ser físicamente activos.The aims of this study were: (a) to know the psychometric properties of the intention of being physically active adapted scale to primary education, and (b) to verify this measurement in the same educative stage. Seventy hundred fifty seven students were deliberately selected. The investigation was divided in two parts. First, the instrument was initially adapted, 12 expert judges were consulted to obtain content validity, and 24 children to obtain understanding validity. Second, the instrument was administered and the data were obtained. With regard the first aim, the experts and children suggested the adaptation and clarification of four items. Exploratory factorial analysis reported that all the items were grouped in a factor (explained variance = 50.88%) and confirmatory factor analysis was acceptable (χ2/g. l. = 4.83; CFI = .93; GFI = .91; RMSEA = .06). The instrument had a high internal consistency (a = .80) and temporal reliability (ICC = .79). With regard the second aim, the participants reported a high intention of being physically active (3.94). The age variable influenced in the prediction of intention of being physically active (B = .529; ET = .192; p = .006). The intention of being physically active to 11-12 years old participants was greater with respect to those of 9-10 years old (F = 8.684; d. f. = 1; p = 0.003; η2 = 0.013). In conclusion, this study displays a valid, reliable, and easy instrument to know the primary students future intention of being physically active. The participants showed high values of intention of being physically active, and in particular, the values were higher in the higher years old participants

GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration

Increased GSK-3 activity is believed to contribute to the etiology of chronic disorders like Alzheimer’s disease (AD), schizophrenia, diabetes, and some types of cancer, thus supporting therapeutic potential of GSK-3 inhibitors. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this review we have focused on the relevance of these mouse models for the study of the role of GSK-3 in apoptosis. GSK-3 is involved in two apoptotic pathways, intrinsic and extrinsic pathways, and plays opposite roles depending on the apoptotic signaling process that is activated. It promotes cell death when acting through intrinsic pathway and plays an anti-apoptotic role if the extrinsic pathway is occurring. It is important to dissect this duality since, among the diseases in which GSK-3 is involved, excessive cell death is crucial in some illnesses like neurodegenerative diseases, while a deficient apoptosis is occurring in others such as cancer or autoimmune diseases. The clinical application of a classical GSK-3 inhibitor, lithium, is limited by its toxic consequences, including motor side effects. Recently, the mechanism leading to activation of apoptosis following chronic lithium administration has been described. Understanding this mechanism could help to minimize side effects and to improve application of GSK-3 inhibitors to the treatment of AD and to extend the application to other diseases.Peer reviewedPeer Reviewe

Ambiguities in scientific terms: The use of “error” and “bias” in statistics

El uso correcto de la estadística es clave para los profesionales que responden preguntas a partir de datos; entre ellos están los ecólogos. Sin embargo, a estos profesionales, la estadística les suele resultar confusa; en parte, esto se debe a dificultades relacionadas con la terminología. Muchas de estas dificultades derivan de los múltiples significados que tiene un término, tanto dentro como fuera del ámbito estadístico. Para los profesionales de habla hispana, la traducción de términos desde el inglés también aporta a esta confusión. En este trabajo exponemos (e intentamos clarificar) algunos de estos problemas a partir de dos de los términos que conforman la base de un curso de estadística introductorio: error y sesgo. Estos términos son discutidos en los diferentes contextos que se atraviesan en la resolución de problemas utilizando la estadística: muestreo, medición, inferencia y predicción. El error es inherente a la estadística y, según el contexto, se lo usa para cuantificar distintos tipos de variabilidad o para indicar la posibilidad de equivocarse al tomar una decisión. El sesgo, en cambio, refleja la tendencia hacia ciertos valores o elementos y, de no evitarse, conlleva a conclusiones erróneas. Proponemos que los problemas asociados con la ambigüedad léxica se aborden desde la enseñanza universitaria, y sobre esa base brindamos algunas recomendaciones. En este sentido, si bien el presente artículo provee una guía para que los profesionales hagan un uso adecuado de algunos términos estadísticos, también brinda un aporte para el ejercicio docente.The proper use of statistics is key for professionals who answer questions from data, including ecologists. However, statistics is generally confusing for these professionals, in part due to difficulties related to its terminology. Many of these difficulties derive from the multiple meanings that a term has, both inside and outside the statistical scope. For Spanish-speaking professionals, the translation of English terms also contributes to this confusion. In this paper we show (and intend to clarify) some of these problems from two key terms of an introductory statistics course: error and bias. These terms are discussed in the different contexts that involve problem resolution using statistics: sampling, measurement, estimation, inference and prediction. Error is inherent to statistics and is used to quantify different types of variability or to indicate the possibility of making mistakes on decision making, depending on the context. On the other hand, bias reflects the tendency towards certain values and/or elements, and leads to erroneous conclusions if not avoided. We propose that the problems associated with lexical ambiguity should to be addressed from university teaching and based on this, we offer some recommendations. Thus, the present article not only offers a guide for professionals to make an adequate use of some statistical terms but also provides a contribution for teaching.Fil: Oddi, Facundo José. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Negro. Sede Andina; ArgentinaFil: Aristimuño, Francisco Javier. Universidad Nacional de Río Negro. Sede Andina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Coulin, Carolina. Universidad Nacional de Río Negro. Sede Andina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garibaldi, Lucas Alejandro. Universidad Nacional de Río Negro. Sede Andina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

A nonlinear superposition rule for solutions of the Milne--Pinney equation

A superposition rule for two solutions of a Milne--Pinney equation is derived.Comment: 14 pages, 2 figure

Synchronous firing of dorsal horn neurons at the origin of dorsal root reflexes in naïve and paw-inflamed mice

Spinal interneurons located in the dorsal horn induce primary afferent depolarization (PAD) controlling the excitability of the afferent?s terminals. Following inflammation, PAD may reach firing threshold contributing to maintain inflammation and pain. Our aim was to study the collective behavior of dorsal horn neurons, its relation to backfiring of primary afferents and the effects of a peripheral inflammation in this system. Experiments were performed on slices of spinal cord obtained from naïve adult mice or mice that had suffered an inflammatory pretreatment. Simultaneous recordings from groups of dorsal horn neurons and primary afferents were obtained and machine-learning methodology was used to analyze effective connectivity between them. Dorsal horn recordings showed grouping of spontaneous action potentials from different neurons in ?population bursts.? These occurred at irregular intervals and were formed by action potentials from all classes of neurons recorded. Compared to naïve, population bursts from treated animals concentrated more action potentials, had a faster onset and a slower decay. Population bursts were disrupted by perfusion of picrotoxin and held a strong temporal correlation with backfiring of afferents. Effective connectivity analysis allowed pinpointing specific neurons holding pre- or post-synaptic relation to the afferents. Many of these neurons had an irregular fast bursting pattern of spontaneous firing. We conclude that population bursts contain action potentials from neurons presynaptic to the afferents which are likely to control their excitability. Peripheral inflammation may enhance synchrony in these neurons, increasing the chance of triggering action potentials in primary afferents and contributing toward central sensitization.Ministerio de Ciencia e InnovaciónUniversidad de Alcal