Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Background: While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. Methods: To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/ PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ ™ Gelatin, and vascular functionality. Results: We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Conclusions: Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.University of Cadiz Predoctoral FellowshipEuropean CommissionEuropean Commission Joint Research Centre GA 847749Programa Estatal de Generacion de Conocimiento y Fortalecimiento Cientifico y Tecnologico del Sistema de I + D + i y del Programa Estatal de I + D +i Orientada a los Retos de la Sociedad, del Plan Estatal de Investigacion Cientifica y Tecnica y de Innovaci PID2020-115499RB-I00/AEIAgencia Estatal de Investigacion (AEI) BFU 2016-75038-REuropean CommissionSpanish Government Spanish GovernmentAndalucia se mueve con Europa P20-0092

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia–metabolism interface.30 página

Alzheimer's Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models

Alzheimer's disease (AD) is the most common cause of dementia. Epidemiological studies show the association between AD and type 2 diabetes (T2DM), although the mechanisms are not fully understood. Dietary habits and lifestyle, that are risk factors in both diseases, strongly modulate gut microbiota composition. Also, the brain-gut axis plays a relevant role in AD, diabetes and inflammation, through products of bacterial metabolism, like short-chain fatty acids. We provide a comprehensive review of current literature on the relation between dysbiosis, altered inflammatory cytokines profile and microglia in preclinical models of AD, T2DM and models that reproduce both diseases as commonly observed in the clinic. Increased proinflammatory cytokines, such as IL-1 beta and TNF-alpha, are widely detected. Microbiome analysis shows alterations in Actinobacteria, Bacteroidetes or Firmicutes phyla, among others. Altered alpha- and beta-diversity is observed in mice depending on genotype, gender and age; therefore, alterations in bacteria taxa highly depend on the models and approaches. We also review the use of pre- and probiotic supplements, that by favoring a healthy microbiome ameliorate AD and T2DM pathologies. Whereas extensive studies have been carried out, further research would be necessary to fully understand the relation between diet, microbiome and inflammation in AD and T2DM

Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline

Cognitive decline; Cortex; MetabolismDeclivi cognitiu; Còrtex; MetabolismeDeterioro cognitivo; Corteza; MetabolismoAims/hypothesis Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets. Methods Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the findings from scRNA-seq and to investigate whether these cell-specific dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes. Results Compared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in post-mortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density. Conclusions/interpretation Taken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Amyloid; Multiphoton microscopy; PrediabetesAmiloide; Microscòpia multifotònica; PrediabetisAmiloide; Microscopía multifotónica; PrediabetesBackground While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. Methods To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality. Results We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Conclusions Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.University of Cadiz Predoctoral Fellowship (CHB). This study is part of the current project (RECOGNISED; Clinical Trials gov registration no. NCT04281186) funded by the European Commission (H2020 programme-GA 847749) focusing on common mechanisms in the pathogenesis of diabetic retinopathy, brain pathology and cognitive impairment, with special interest in the neurovascular unit, in the T2D population. Agencia Estatal de Investigacion. Ministerio de Ciencia e Innovacion. Programa Estatal de Generacion de Conocimiento y Fortalecimiento Cientifico y Tecnologico del Sistema de I + D + i y del Programa Estatal de I + D + i Orientada a los Retos de la Sociedad, del Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion (PID2020-115499RB-I00/AEI/10.130 39/501100011033). Programa Estatal de I + D + I orientada a los Retos de la Sociedad (BFU 2016-75038-R), financed by the Agencia Estatal de Investigacion (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Economia y Competitividad. Proyectos de I + D + i, en regimen de concurrencia competitiva, destinadas a las universidades y entidades publicas de investigacion calificadas como agentes del Sistema Andaluz del Conocimiento, en el ambito del Plan Andaluz de Investigacion, Desarrollo e Innovación (PAIDI 2020). Andalucia se mueve con Europa (P20-00928)

Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer's Disease and Type 2 Diabetes

Alzheimer's disease is the most common form of dementia, and epidemiological studies support that type 2 diabetes (T2D) is a major contributor. The relationship between both diseases and the fact that Alzheimer's disease (AD) does not have a successful treatment support the study on antidiabetic drugs limiting or slowing down brain complications in AD. Among these, liraglutide (LRGT), a glucagon-like peptide-1 agonist, is currently being tested in patients with AD in the Evaluating Liraglutide in Alzheimer's Disease (ELAD) clinical trial. However, the effects of LRGT on brain pathology when AD and T2D coexist have not been assessed. We have administered LRGT (500 mu g/kg/day) to a mixed murine model of AD and T2D (APP/PS1xdb/db mice) for 20 weeks. We have evaluated metabolic parameters as well as the effects of LRGT on learning and memory. Postmortem analysis included assessment of brain amyloid-beta and tau pathologies, microglia activation, spontaneous bleeding and neuronal loss, as well as insulin and insulin-like growth factor 1 receptors. LRGT treatment reduced glucose levels in diabetic mice (db/db and APP/PS1xdb/db) after 4 weeks of treatment. LRGT also helped to maintain insulin levels after 8 weeks of treatment. While we did not detect any effects on cortical insulin or insulin-like growth factor 1 receptor m-RNA levels, LRGT significantly reduced brain atrophy in the db/db and APP/PS1xdb/db mice. LRGT treatment also rescued neuron density in the APP/PS1xdb/db mice in the proximity (p = 0.008) far from amyloid plaques (p < 0.001). LRGT reduced amyloid plaque burden in the APP/PS1 animals (p < 0.001), as well as A beta aggregates levels (p = 0.046), and tau hyperphosphorylation (p = 0.009) in the APP/PS1xdb/db mice. Spontaneous bleeding was also ameliorated in the APP/PS1xdb/db animals (p = 0.012), and microglia burden was reduced in the proximity of amyloid plaques in the APP/PS1 and APP/PS1xdb/db mice (p < 0.001), while microglia was reduced in areas far from amyloid plaques in the db/db and APP/PS1xdb/db mice (p < 0.001). This overall improvement helped to rescue cognitive impairment in AD-T2D mice in the new object discrimination test (p < 0.001) and Morris water maze (p < 0.001). Altogether, our data support the role of LRGT in reduction of associated brain complications when T2D and AD occur simultaneously, as regularly observed in the clinical arena.CH-B: predoctoral fellowship. University of Cadiz. PA-M: predoctoral fellowship. Instituto de Investigacion Biomedica de la Provincia de Cadiz (INIBICA). MG-A: Agencia Estatal de Investigacion. Ministerio de Ciencia e Innovacion. Programa Estatal de Generacion de Conocimiento y Fortalecimiento Cientifico y Tecnologico del Sistema de I C D C i y del Programa Estatal de I + D + i Orientada a los Retos de la Sociedad, del Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2017-2020 (PID2020115499RB-I0). Programa Estatal de I C D C I orientada a los Retos de la Sociedad (BFU 2016-75038-R), financed by the Agencia Estatal de Investigacion (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Ciencia, Innovacion y Universidades. Subvencion para la financiacion de la Investigacion y la Innovacion Biomedica y en Ciencias de la Salud en el Marco de la Iniciativa Territorial Integrada 2014-2020 para la Provincia de Cadiz. Consejeria de Salud. Junta de Andalucia. Union Europea, financed by the Fondo de Desarrollo Regional (FEDER) (PI-0008-2017)

Representaciones sociales sobre la ingerencia municipal, en la vocación territorial de los departamentos Zonda y Pocito (Provincia de San Juan)

En el marco de referencia del trabajo se vinculan los conceptos de “representaciones sociales” con el de “vocación territorial” utilizando como sopor te para el análisis el rol que el municipio cumple en el contexto comunal. Para ello, se trabaja con las representaciones sociales, como sistemas cognoscitivos, como sistemas de valores, ideas y prácticas en su doble función: orientar a los individuos en su mundo material y social y posibilitar la comunicación entre los miembros de una comunidad proporcionándoles códigos compartidos. Y, con la vocación territorial, como el conjunto de aptitudes, disposiciones y potencialidades de un territorio, el cual es considerado como el medio físico socialmente construido, sobre una naturaleza dada, del sistema de soportes materiales de una sociedad concreta, cambiante dinámica y contradictoria. En este marco se apunta, por un lado, a identificar el rol del municipio en relación al desarrollo y potenciación de la vocación de su territorio y, por otro, detectar las representaciones sociales de los miembros de la comunidad, que se desempeñan en las diferentes áreas de la actividad económica de cada territorio; en relación al rol municipal, como gerenciador o promotor de t ales actividades. Esto es, conocer las opiniones, percepciones y valores de la comunidad respecto al apoyo, interés o indiferencia que reciben del mismo. El contexto de referencia son dos departamentos, con características diferentes, a fin de realizar una posterior comparación de la situación que presenta cada uno de ellos

Evaluación del currículo ofertado por la Universidad Estatal Amazónica para la carrera de Ingeniería en Turismo

El currículo, para ser exitoso y de calidad, debe estar siendo evaluado permanentemente, con intención de mejorarlo y lograr así la plena formación del estudiantado. Esta se hace cada vez más importante, debido a que permite generar y obtener logros significativos en el proceso educacional en pro de un perfeccionamiento racional y científicamente válido para enfrentar los desafíos actuales. El objetivo de esta investigación fue realizar la evaluación curricular de la carrera de turismo de la UEA, a través de una metodología con enfoque epistemológico orientado al cambio. Se utilizó el método de la investigación acción participante, que consiste en un proceso sistemático que requiere la participación de todos los actores involucrados en el proceso de enseñanza aprendizaje (internos y externos), quienes tienen el conocimiento más profundo de sus problemas y su realidad. Los resultados de la investigación muestran los hallazgos, fallas, debilidades y aciertos que orientaron la toma de decisión para realizar los ajustes pertinentes y favorecer la calidad de la enseñanza, que es uno de los grandes desafíos de la educación superior del siglo XXI

Dispositivos móviles como soporte para el aprendizaje colaborativo de Programación en el nivel universitario inicial (resultados parciales)

El presente proyecto propone como objetivo central estudiar la incidencia de estrategias colaborativas para el aprendizaje de Programación en el nivel universitario inicial utilizando tecnologías móviles y plataformas de educación a distancia. Para esto se propone realizar un estudio de caso en la cátedra Elementos de Programación de las carreras de Análisis de Sistemas de Información y Tecnicatura Universitaria en Programación de la Facultad de Ciencias Exactas, UNSa. La incorporación de TICs en el aula conlleva un necesario proceso de resignificación de la práctica docente, en este caso particular, poniendo énfasis en contextos colaborativos. Los recursos tecnológicos a incorporar están basados en aplicaciones para dispositivos móviles y plataformas de educación a distancia y desarrollados a medida por integrantes del equipo en base a lineamentos surgidos de la propia investigación respecto del diseño del contexto colaborativo. En este trabajo se presentan las ideas generales del proyecto y los avances alcanzados hasta la fecha.Eje: Tecnología Informática Aplicada en EducaciónRed de Universidades con Carreras en Informática (RedUNCI

Dispositivos móviles como soporte para el aprendizaje colaborativo de Programación en el nivel universitario inicial (resultados parciales)

El presente proyecto propone como objetivo central estudiar la incidencia de estrategias colaborativas para el aprendizaje de Programación en el nivel universitario inicial utilizando tecnologías móviles y plataformas de educación a distancia. Para esto se propone realizar un estudio de caso en la cátedra Elementos de Programación de las carreras de Análisis de Sistemas de Información y Tecnicatura Universitaria en Programación de la Facultad de Ciencias Exactas, UNSa. La incorporación de TICs en el aula conlleva un necesario proceso de resignificación de la práctica docente, en este caso particular, poniendo énfasis en contextos colaborativos. Los recursos tecnológicos a incorporar están basados en aplicaciones para dispositivos móviles y plataformas de educación a distancia y desarrollados a medida por integrantes del equipo en base a lineamentos surgidos de la propia investigación respecto del diseño del contexto colaborativo. En este trabajo se presentan las ideas generales del proyecto y los avances alcanzados hasta la fecha.Eje: Tecnología Informática Aplicada en EducaciónRed de Universidades con Carreras en Informática (RedUNCI