Complicaciones centrales en un modelo murino de enfermedad de alzheimer y diabetes mellitus: papel de la liraglutida

La enfermedad de Alzheimer (EA) es la causa más común de demencia. Se caracteriza neuropatológicamente por el depósito del péptido β-amiloide (βA), la presencia de ovillos neurofibrilares y una profunda pérdida neuronal y sináptica. Si bien el principal factor de riesgo para padecer EA es la edad, múltiples estudios demuestran que las alteraciones metabólicas, y concretamente la diabetes mellitus tipo 2 (DM2), tienen un papel relevante. Con el fin de profundizar en los mecanismos que relacionan las alteraciones metabólicas producidas por la DM2 y la EA, nuestro laboratorio ha desarrollado un modelo murino mixto de EA y DM2 (el ratón APP/PS1xdb/db). Este modelo animal permite valorar el papel de las alteraciones metabólicas en el sistema nervioso central y específicamente en la EA. Por otro lado, en la actualidad, la EA no tiene un tratamiento exitoso y por ello es necesaria la búsqueda de alternativas terapéuticas que puedan prevenir, retrasar o tratar esta patología. Aunque con limitaciones, la DM2 cuenta con diversos tratamientos. Teniendo en cuenta la relación entre ambas patologías y la necesidad de un tratamiento eficaz para la EA, resultan interesantes estudios sobre fármacos antidiabéticos que limiten o ralenticen las complicaciones cerebrales de la EA. Entre estos se incluyen agonistas del péptido similar al glucagón, como la liraglutida (LRGT). Estudios previos han mostrado que la LRGT puede mejorar las alteraciones del sistema nervioso central en modelos animales de EA, aunque no conocemos estudios en los que se valore su papel en la patología cerebral cuando la EA y la DM2 coexisten. Además, en la actualidad se está probando la LRGT en pacientes con EA en el ensayo clínico Evaluating Liraglutide in Alzheimer's Disease (ELAD). En este trabajo hemos compendiado los estudios que analizan el papel de la LRGT en la EA, centrándonos en modelos animales de la enfermedad y su función a nivel cognitivo y en la patología tipo Alzheimer. Estos artículos han sido analizados y recopilados en un artículo de revisión. Además, hemos estudiado el efecto tratamiento con LRGT a largo plazo (administrado entre las 6 y 26 semanas de edad) en las alteraciones cognitivas, daño central y alteraciones metabólicas en modelos murinos de EA, DM2 y en el modelo mixto de EA y DM2. El tratamiento con LRGT redujo los niveles de glucosa en ratones diabéticos (db/db y APP/PS1xdb/db). La LRGT también ayudó a mantener los niveles de insulina en el rango normal. Si bien no se detectó ningún efecto sobre los niveles de ARNm del receptor del factor de crecimiento similar a la insulina 1, la LRGT redujo significativamente la atrofia cerebral en los ratones db/db y APP/PS1xdb/db. El tratamiento con LRGT también mejoró la densidad neuronal en los ratones APP/PS1xdb/db en la proximidad y lejos de las placas amiloides. La LRGT redujo la carga de placas amiloides en los animales APP/PS1 así como los niveles de βA oligomérico y la hiperfosforilación de tau en los ratones APP/PS1xdb/db. Las hemorragias espontáneas también mejoraron en los animales APP/PS1xdb/db, y la carga de microglía se redujo en la proximidad de las placas amiloides en los ratones APP/PS1 y APP/PS1xdb/db y en áreas alejadas de las placas amiloides en los ratones db/db y APP/PS1xdb/db. Esta mejora general ayudó a limitar el deterioro cognitivo en ratones modelo de EA y DM2 en la prueba de discriminación de nuevo objeto y en el laberinto acuático de Morris. En conjunto, nuestros datos respaldan el papel de LRGT en la reducción de las complicaciones cerebrales asociadas cuando la DM2 y la EA ocurren simultáneamente, como se observa regularmente en el ámbito clínico

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

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer's disease and type 2 diabetes

Background Both Alzheimer's disease (AD) and type 2 diabetes (T2D) share common pathological features including inflammation, insulin signaling alterations, or vascular damage. AD has no successful treatment, and the close relationship between both diseases supports the study of antidiabetic drugs to limit or slow down brain pathology in AD. Empagliflozin (EMP) is a sodium-glucose co-transporter 2 inhibitor, the newest class of antidiabetic agents. EMP controls hyperglycemia and reduces cardiovascular comorbidities and deaths associated to T2D. Therefore, we have analyzed the role of EMP at the central level in a complex mouse model of AD-T2D. Methods We have treated AD-T2D mice (APP/PS1xdb/db mice) with EMP 10 mg/kg for 22 weeks. Glucose, insulin, and body weight were monthly assessed. We analyzed learning and memory in the Morris water maze and the new object discrimination test. Postmortem brain assessment was conducted to measure brain atrophy, senile plaques, and amyloid-beta levels. Tau phosphorylation, hemorrhage burden, and microglia were also measured in the brain after EMP treatment. Results EMP treatment helped to maintain insulin levels in diabetic mice. At the central level, EMP limited cortical thinning and reduced neuronal loss in treated mice. Hemorrhage and microglia burdens were also reduced in EMP-treated mice. Senile plaque burden was lower, and these effects were accompanied by an amelioration of cognitive deficits in APP/PS1xdb/db mice. Conclusions Altogether, our data support a feasible role for EMP to reduce brain complications associated to AD and T2D, including classical pathological features and vascular disease, and supporting further assessment of EMP at the central level

The Impact of Clinical Training Seminars on Stress and Perception of Clinical Placement Stressors among Spanish Undergraduate Nursing Students: A Two-Phase Mixed-Methods Study

Stress and stressors related to clinical practice are some of the main reasons for the discomfort reported by nursing students. It is important to identify the causes of stress and seek strategies to reduce the stress levels in nursing students. Clinical training seminars have proven to be a useful tool to reduce stress levels. This study aims to evaluate the effects of a series of clinical training seminars on the levels of stress and perception of stress factors before the start of clinical practice among undergraduate Spanish nursing students. A two-phase, sequential mixed-methods design was used. For the quantitative phase, data were collected using Cohen’s Perceived Stress Scale and the KEZKAK questionnaire before and after the clinical training seminars. Qualitative data were collected through a focus group session held after the clinical training period. The results show a significant reduction (p = 0.002) in perceived stress levels after the clinical training seminars, and also a change in students’ perception of stressors in the clinical placement. This study provides valuable information for the development of content for clinical training seminars. Universities should develop strategies to reduce stress in their students caused by the clinical placement.13 página

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)

The Impact of Clinical Training Seminars on Stress and Perception of Clinical Placement Stressors among Spanish Undergraduate Nursing Students: A Two-Phase Mixed-Methods Study

Stress and stressors related to clinical practice are some of the main reasons for the discomfort reported by nursing students. It is important to identify the causes of stress and seek strategies to reduce the stress levels in nursing students. Clinical training seminars have proven to be a useful tool to reduce stress levels. This study aims to evaluate the effects of a series of clinical training seminars on the levels of stress and perception of stress factors before the start of clinical practice among undergraduate Spanish nursing students. A two-phase, sequential mixed-methods design was used. For the quantitative phase, data were collected using Cohen&rsquo;s Perceived Stress Scale and the KEZKAK questionnaire before and after the clinical training seminars. Qualitative data were collected through a focus group session held after the clinical training period. The results show a significant reduction (p = 0.002) in perceived stress levels after the clinical training seminars, and also a change in students&rsquo; perception of stressors in the clinical placement. This study provides valuable information for the development of content for clinical training seminars. Universities should develop strategies to reduce stress in their students caused by the clinical placement