Efectos de la acumulación del péptido Beta amiloide en tejido cerebral de ratones PS1xAPP modelos de la Enfermedad de Alzheimer

Esta enfermedad se ha convertido en el tercer problema de salud más grave en los países desarrollados (detrás de los accidentes cardiovasculares y el cáncer). Existen alrededor de 800.000 enfermos diagnosticados en España y 45 millones a nivel mundial. Aunque parezca imposible, estas cifras sufrirán un incremento en el futuro debido al aumento progresivo de la esperanza de vida actual, al envejecimiento de la población, de forma que se pronostica que en el año 2050 unos 115 millones de personas en el mundo se encontrarán afectadas por esta enfermedad. Por todo esto la EA es un gran problema de salud pública, agravado por el elevado coste económico, sanitario y social que supone el cuidado de un enfermo de EA. Esta enfermedad se caracteriza por unos rasgos anatómico patológicos distintivos. Por un lado están las alteraciones macroscópicas, entre las que podemos encontrar: atrofia cortical severa, adelgazamiento de las circunvoluciones y ensanchamiento de los surcos, engrosamiento de las meninges, dilatación de las cavidades ventriculares, disminución del bulbo olfatorio y pérdida de peso y volumen cerebral; y por otro las microscópicas, que incluyen: son los agregados proteicos extracelulares en forma de placa del péptido β-amiloide, los ovillos neurofibrilares intraneuronales de la proteína TAU hiperfosforilada, la disminución del número de sinapsis y la degeneración neuronal en las áreas cerebrales afectadas. Es de vital importancia el estudio de cómo surge y progresa la patología de EA, para poder identificar posibles dianas terapéuticas que permita el desarrollo de fármacos que impidan, o al menos retrase, la progresión de la enfermedad. Para tal fin se han desarrollado los modelos animales de la Enfermedad de Alzheimer. En los últimos años se están desarrollando mucho de estos modelos, y aunque ninguno de ellos reproduce la totalidad de la patología de EA observada en humanos, están proporcionando una valiosa información sobre la patogénesis de la misma. Nuestro trabajo se desarrolla con el modelo transgénico PS1M146L/APPSL (las formas mutadas de los genes humanos presenilina y de la proteína precursora del péptido β-amiloide, mutaciones detectadas en casos de Alzheimer familiar). Atendiendo a la hipótesis inflamatoria, que propone que ésta contribuye a la patogénesis inicial de la EA hemos caracterizado la respuesta microglial en el hipocampo de estos animales, en relación con la aparición y acumulación del péptido β-amiloide y de sus distintas especies (ya sea en placas extracelulares insolubles, o de las formas oligoméricas solubles que pueden difundir por todo el parénquima). Nuestros datos muestran una coexistencia espacio-temporal de la activación de la microglía con la acumulación de placas extracelulares (desde edades tempranas), pero también con el inicio de la aparición y acumulación de las formas solubles de Aβ (a edades más avanzadas), generando ambas formas de Aβ un fenotipo de activación totalmente antagónicos en las células microgliales. El estudio ha continuado con la evaluación del efecto que tiene las fracciones solubles extracelulares (fracciones S1) obtenidas de la corteza de los ratones PS1xAPP de distintas edades sobre la vía pro supervivencia PI3K-Akt- GSK-3β. Las fracciones S1 de animales jóvenes, en las cuales aún no se detectan formas oligoméricas solubles del péptido Aβ, activan esta ruta generando un ambiente neuro-protector; mientras que las fracciones S1 de animales viejos las inhiben, haciendo más vulnerables a las neuronas. Teniendo en cuenta la importancia de estas formas solubles de Aβ, hemos realizado estudios de los protocolos actuales que se llevan a cabo para su determinación en tejidos post mortem, ya que es importante poder evaluar correctamente la presencia fisiología de los mismos en el parénquima cerebral. Para terminar hemos realizado un tratamiento crónico con Litio en nuestro modelo PS1xAPP, a edades tempranas, incluso antes de que comience la patología de Aβ (3 meses) para su posible uso como terapia preventiva en personas con riesgo de padecer EA, o con deterioro cognitivo leve.Premio Extraordinario de Doctorado U

The effects of human-game interaction, network externalities, and motivations on players’ use of mobile casual games.

Purpose - This paper empirically examines the factors that influence the acceptance and use of mobile casual games. Methodology - A theoretical model is proposed based on the theory of reasonable action, the uses and gratifications theory, the network externalities paradigm and the human-computer interaction literature. An empirical study was conducted through an online survey of mobile casual gamers in Spain, using a convenience sample. The proposed model was tested by an analysis of the collected data through a structural equation model using the partial least squares (PLS) method. Findings - The results indicate that human-mobile game interaction and network externalities have a significant indirect impact on intention to play, through utilitarian, hedonic and relational motivations. In addition, the full mediation effect of attitude was found between these constructs and intention to play, which is a very important determinant of actual use. Originality/value - This study is among the few that focuses on users’ acceptance of mobile games apps, the features of which differ significantly from personal computer and console games. It highlights the effects of human-game interaction and network externalities on the adoption of mobile casual games. Hence, the study contributes to the theoretical and practical understanding of the factors that lead users to adopt an entertainment mobile application.This work was supported by the Andalusia Regional Government [Excellence Research Project P12-SEJ-1980]; and the Spanish Ministry of Economy and Competitiveness [Project ECO2012-39576]

1–42 b -Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death

1–42 b -Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death L Manterola 1,12 , M Hernando-Rodr ı ́ guez 2,12 , A Ruiz 3,4 , A Apraiz 5 , O Arrizabalaga 5 , L Vello ́ n 6 , E Alberdi 3,4 , F Cavaliere 3,4 , HM Lacerda 7 , S Jimenez 8,9 , LA Parada 10 , C Matute 3,4 and JL Zugaza 4,5,11 1–42 b -Amyloid (A b 1–42 ) peptide is a key molecule involved in the development of Alzheimer’s disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of A b 1–42 peptide activation of the neurodegenerative program is still poorly understood. Here, A b 1–42 peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/ phosphoinositol-dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of A b 1–42 peptide in neurons

Caracterización bioacústica de las llamadas de apareamiento de un pez de agua dulce (Prochilodus magdalenae) para monitoreo acústico pasivo

Fish produce sounds that are usually species-specific and associated with particular behaviors and contexts. Acoustic characterization enables the use of sounds as natural acoustic labels for species identification. Males of Prochilodus magdalenae produce mating sounds. We characterized  these sounds and tested their use in natural habitats, to use passive acoustic monitoring for spawning ground identification. We identified two types of acoustic signals: simple pulses and pulse trains. Simple pulses were 13.7 ms long, with peak frequency of 365 Hz, whereas pulse train were 2.3 s long, had peak frequency of 399 Hz, 48.6 pulses and its pulses lasted 12.2 ms, with interpulse interval of 49.0 ms long and 22.3 Hz pulse rate. We did not detect spawning in  absence of male calls nor differences in male sounds at different female densities. We found differences in train duration, pulse rate, and pulse duration in trains, according to the fish's source sites, but these sites were not well discriminated based on bioacoustical variables. In rivers, we located two P. magdalenae spawning grounds and recognized calls from another fish species (Megaleporinus muyscorum). We did not find a significant relationship between fish size and call peak frequency for P. magdalenae.Los peces producen sonidos que generalmente están asociados con comportamientos y contextos particulares y son especie-específicos. Su caracterización permite usarlos como etiquetas acústicas naturales para identificar especies. Los machos de Prochilodus magdalenae emiten sonidos de apareamiento. Caracterizamos estas señales acústicas y probamos su uso en hábitats naturales, para utilizar el monitoreo acústico pasivo para la identificación de zonas de desove. Identificamos dos tipos de señales acústicas: pulsos simples y trenes de pulsos. Los pulsos simples tuvieron una duración de 13.7 ms y frecuencia pico de 365 Hz, mientras que los trenes de pulsos duraron 2.3 s,  frecuencia pico de 399 Hz, 48.6 pulsos por tren, pulsos de 12.2 ms, intervalo interpulso de 49.0 ms y tasa de pulsos de 22.3 Hz. No detectamos desove en ausencia de sonidos de machos ni diferencias acústicas entre machos en parejas o en grupos de hembras. Dependiendo del origen de los machos, la duración del tren, frecuencia del pulso y duración del pulso en los trenes difirieron, pero los sitios no fueron bien discriminados basados en las variables bioacústicas. En ríos localizamos dos zonas de desove de P. magdalenae y pudimos distinguir sus sonidos respecto a los del pez Megaleporinus muyscorum. No encontramos una relación significativa entre el tamaño y la frecuencia pico para P. magdalenae

Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

BACKGROUND: In obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model. METHODS: BM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using 1H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay. RESULTS: Four days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC showed an upregulation of cytokine and protein secretion that may explain homing, immunomodulation, and vascular permeability, and therefore the tissue recovering. CONCLUSIONS: BM-MSC treatment in severe congenital hydrocephalus is viable and leads to the recovery of the severe neurodegenerative conditions in the neocortex. NMR spectroscopy allows to follow-up the effects of stem cell therapy in hydrocephalus.España Instituto Carlos III , PI15/00619 (to AJJ), PI19/00778 (to AJJ and PPG), PI15/00796, and PI18/01557España Ministerio de Educación, Cultura y Deporte FPU13/02906España, Ministerio de Economía y Competitividad RYC-2014-16980España, FEDER Andalucía y Universidad de Málaga UMA18-FEDERJA-27

Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology

Microglial cells are crucial players in the pathological process of neurodegenerative diseases, such as Alzheimer’s disease (AD). Microglial response in AD has been principally studied in relation to amyloid-beta pathology but, comparatively, little is known about inflammatory processes associated to tau pathology. In the hippocampus of AD patients, where tau pathology is more prominent than amyloid-beta pathology, a microglial degenerative process has been reported. In this work, we have directly compared the microglial response in two different transgenic tau mouse models: ThyTau22 and P301S. Surprisingly, these two models showed important differences in the microglial profile and tau pathology. Where ThyTau22 hippocampus manifested mild microglial activation, P301S mice exhibited a strong microglial response in parallel with high phospho-tau accumulation. This differential phospho-tau expression could account for the different microglial response in these two tau strains. However, soluble (S1) fractions from ThyTau22 hippocampus presented relatively high content of soluble phospho-tau (AT8-positive) and were highly toxic for microglial cells in vitro, whereas the correspondent S1 fractions from P301S mice displayed low soluble phosphotau levels and were not toxic for microglial cells. Therefore, not only the expression levels but the aggregation of phospho-tau should differ between both models. In fact, most of tau forms in the P301S mice were aggregated and, in consequence, forming insoluble tau species.We conclude that different factors as tau mutations, accumulation, phosphorylation, and/or aggregation could account for the distinct microglial responses observed in these two tau models. For this reason, deciphering the molecular nature of toxic tau species for microglial cells might be a promising therapeutic approach in order to restore the deficient immunological protection observed in AD hippocampus.CIBERNEDJunta de Andalucía. Consejería de Economía, Innovación, Ciencia y Empleo CTS-2035Fundación Tatiana Pérez de Guzmán el BuenoMinisterio de Ciencia, Innovación y UniversidadesInstituto de Salud Carlos III. Fondo de Investigación Sanitaria. PI15/00957 PI15/00796Fondo Europeo de Desarrollo Regional PI15/00957 PI15/0079

Graft-versus-host disease affecting oral cavity: a review

Graft versus host disease (GVHD) is one of the most frequent and serious complications of hematopoietic stem cell transplantation, and is regarded as the leading cause of late mortality unrelated to the underlying malignant disease. GVHD is an autoimmune and alloimmune disorder that usually affects multiple organs and tissues, and exhibits a variable clinical course. It can manifest in either acute or chronic form. The acute presentation of GVHD is potentially fatal and typically affects the skin, gastrointestinal tract and liver. The chronic form is characterized by the involvement of a number of organs, including the oral cavity. Indeed, the oral cavity may be the only affected location in chronic GVHD. The clinical manifestations of chronic oral GVHD comprise lichenoid lesions, hyperkeratotic plaques and limited oral aperture secondary to sclerosis. The oral condition is usually mild, though moderate to severe erosive and ulcerated lesions may also be seen. The diagnosis is established from the clinical characteristics, though confirmation through biopsy study is sometimes needed. Local corticosteroids are the treatment of choice, offering overall response rates of close to 50%. Extracorporeal photopheresis and systemic corticosteroids in turn constitute second line treatment. Oral chronic GVHD is not considered a determinant factor for patient survival, which is close to 52% five years after diagnosis of the condition

Changes in smoking habit among patients with a history of oral squamous cell carcinoma (OSCC)

Objective: To determine the changes in smoking habit among patients with oral squamous cell carcinoma (OSCC) diagnosed and treated in the Service of Stomatology (Valencia University General Hospital. Valencia, Spain). Material and methods: The study involved 123 patients with a history of OSCC interviewed by telephone on their smoking habits at the time of the diagnosis and modifications in habits subsequently. The mean age at diagnosis was 60 years and 9 months (standard deviation, SD ± 12 years and 2 months). Males predominated (61.8%) over females (38.2%). The mean time from the diagnosis of OSCC to the survey was 4 years and 6 months (SD ± 3 years and 6 months). Results: Almost one-half of the patients (45.5%) were active smokers at the time of the diagnosis, with a mean duration of the habit of 34.9 years (SD ± 12 years and 7 months). In turn, 19.5% of the patients were ex-smokers at diagnosis, with an average of 13 years and 9 months (SD ± 9 years and 4 months) from smoking cessation to the development of cancer. A total of 57.1% of the smokers abandoned the habit at diagnosis, 8.9% continued to smoke to the same extent as before, and 33.9% reduced smoking. Conclusion: A full 44.4 % of our patients diagnosed with OSCC continued to smoke despite warnings of the risks, and although the majority claimed to have reduced their smoking habit, interventional strategies would be indicated to help ensure complete smoking cessation

Sjögren’s syndrome of the oral cavity. Review and update

Sjögren´s syndrome is one of the most frequent autoimmune diseases. It is a chronic and systemic disorder predominantly found in women, and is characterized by the appearance of a lymphocytic inflammatory infiltrate, with dryness of the oral cavity and eyes, secondary to involvement of the salivary and lacrimal glands. The underlying causal mechanism involves a number of factors and has not been clearly established, though an autoimmune response is known to be triggered, with the accumulation of immune complexes in the gland acini that interfere with gland function. In the oral cavity, xerostomia or hyposialia is the most disabling manifestation for patients, and is accompanied by rapidly progressing caries, candidiasis and an important worsening of buccodental health.The most important complication is a 44-fold increase in the risk of developing non-Hodgkin lymphoma, compared with the general population. The treatment of Sjögren’s syndrome is limited to symptomatic management, and involves the use of solutions to replace salivary secretion and afford a measure of hydration, cholinergic agents such as pilocarpine to stimulate the unaffected gland tissue and, recently, the administration of substances that act against surface antigens of the B lymphocytes, such as anti-CD20 and anti-CD22 antibodies. The present study provides an update on this disease, placing special emphasis on its odontologic implications