Grupos Investigadores

Líneas de Investigación

  • Neuroinflamación
  • Modelos experimentales basados en factores de riesgo de la enfermedad de Alzheimer
  • Búsqueda de nuevas estrategias terapéuticas
  • Biomarcadores
  • Alteraciones conductales de la enfermedad de Alzheimer: depresión

Palabras Clave

  • Tau
  • Plasticidad sináptica
  • Neuroprotección
  • Neuroimagen
  • Metalolismo
  • Estrés
  • Epigenética
  • Depresión
  • Demencia
  • Canabinoides
  • Amiloide
  • Alzheimer

Publicaciones Científicas desde 2018

  • Autores: Janeiro Arenas, Manuel Humberto; Ramírez Gil, María Javier; Solas Zubiaurre, Maite (Autor de correspondencia)
    Revista: CELLULAR AND MOLECULAR NEUROBIOLOGY
    ISSN 0272-4340 Vol.42 N° 2 2022 págs. 377 - 387
    Resumen
    Recent investigations have increased the interest on the connection between the microorganisms inhabiting the gut (gut microbiota) and human health. An imbalance of the intestinal bacteria representation (dysbiosis) could lead to different diseases, ranging from obesity and diabetes, to neurological disorders including Alzheimer's disease (AD). The term "gut-brain axis" refers to a crosstalk between the brain and the gut involving multiple overlapping pathways, including the autonomic, neuroendocrine, and immune systems as well as bacterial metabolites and neuromodulatory molecules. Through this pathway, microbiota can influence the onset and progression of neuropathologies such as AD. This review discusses the possible interaction between the gut microbiome and AD, focusing on the role of gut microbiota in neuroinflammation, cerebrovascular degeneration and A beta clearance.
  • Autores: García Osta, Ana María; Dong, J.; Moreno Aliaga, María Jesús; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN 1422-0067 Vol.23 N° 3 2022 págs. 1211
    Resumen
    The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27(Kip1). At the nuclear level, p27(Kip1) has the ability to control the evolution of different phases of the cell cycle and oppose cell cycle progression by binding to CDKs. In the cytoplasm, diverse functions have been described for p27(Kip1), including microtubule remodeling, axonal transport and phagocytosis. In Alzheimer's disease (AD), alterations to cycle events and a purported increase in neurogenesis have been described in the early disease process before significant pathological changes could be detected. However, most neurons cannot progress to complete their cell division and undergo apoptotic cell death. Increased levels of both the p27(Kip1) levels and phosphorylation status have been described in AD. Increased levels of A beta 42, tau hyperphosphorylation or even altered insulin signals could lead to alterations in p27(Kip1) post-transcriptional modifications, causing a disbalance between the levels and functions of p27(Kip1) in the cytoplasm and nucleus, thus inducing an aberrant cell cycle re-entry and alteration of extra cell cycle functions. Further studies are needed to completely understand the role of p27(Kip1) in AD and the therapeutic opportunities associated with the modulation of this target.
  • Autores: Zamarbide González, Marta; Martínez Pinilla, Eva; Gil Bea, Francisco Javier; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN 1422-0067 Vol.23 N° 7 2022 págs. 3533
    Resumen
    The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APP(swe) mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R(-/-)/APP(swe), to perform cognition studies and to assess, by immunoblotting A beta and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R(-/-)/APP(swe) mice do not have the characteristic memory impairment of 12-month-old APP(swe) mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer's disease (AD)-related features, such as amyloid beta (A beta) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3 beta and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks.
  • Autores: Tordera Baviera, Rosa María (Autor de correspondencia); Cortés Erice, María
    Revista: REVIEWS OF PHYSIOLOGY BIOCHEMISTRY AND PHARMACOLOGY
    ISSN 0303-4240 Vol.180 2021 págs. 1 - 47
    Resumen
    Histone deacetylases (HDACs) are a family of 18 members that participate in the epigenetic regulation of gene expression. In addition to histones, some HDACs also deacetylate transcription factors and specific cytoplasmic proteins. Monocytes, as part of the innate immune system, maintain tissue homeostasis and help fight infections and cancer. In these cells, HDACs are involved in multiple processes including proliferation, migration, differentiation, inflammatory response, infections, and tumorigenesis. Here, a systematic description of the role that most HDACs play in these functions is reviewed. Specifically, some HDACs induce a pro-inflammatory response and play major roles in host defense. Conversely, other HDACs reprogram monocytes and macrophages towards an immunosuppressive phenotype. The right balance between both types helps monocytes to respond correctly to the different physiological/pathological stimuli. However, aberrant expressions or activities of specific HDACs are associated with autoimmune diseases along with other chronic inflammatory diseases, infections, or cancer. This paper critically reviews the interesting and extensive knowledge regarding the role of some HDACs in these pathologies. It also shows that as yet, very little progress has been made toward the goal of finding effective HDAC-targeted therapies. However, given their obvious potential, we conclude that it is worth the effort to develop monocyte-specific drugs that selectively target HDAC subtypes with the aim of finding effective treatments for diseases in which our innate immune system is involved.
  • Autores: Janeiro Arenas, Manuel Humberto; García Ardanaz, Carlos; Sola Sevilla, Noemí; et al.
    Revista: ADVANCES IN LABORATORY MEDICINE / AVANCES EN MEDICINA DE LABORATORIO
    ISSN 2628-491X Vol.2 N° 1 2021 págs. 27 - 37
    Resumen
    Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease. AD is the main cause of dementia worldwide and aging is the main risk factor for developing the illness. AD classical diagnostic criteria rely on clinical data. However, the development of a biological definition of AD using biomarkers that reflect the underling neuropathology is needed. Content: The aim of this review is to describe the main outcomes when measuring classical and novel biomarkers in biological fluids or neuroimaging. Summary: Nowadays, there are three classical biomarkers for the diagnosis of AD: Aß42, t-Tau and p-Tau. The diagnostic use of cerebrospinal fluid biomarkers is limited due to invasive collection by lumbar puncture with potential side effects. Plasma/serum measurements are the gold standard in clinics, because they are minimally invasive and, in consequence, easily collected and processed. The two main proteins implicated in the pathological process, Aß and Tau, can be visualized using neuroimaging techniques, such as positron emission tomography. Outlook: As it is currently accepted that AD starts decades before clinical symptoms could be diagnosed, the opportunity to detect biological alterations prior to clinical symptoms would allow early diagnosis or even perhaps change treatment possibilities.
  • Autores: Toledano Illán, Carlos (Autor de correspondencia); Esparragosa Vázquez, Inés; Zelaya Huerta, M. V. ; et al.
    Revista: JOURNAL OF NEUROLOGY
    ISSN 0340-5354 Vol.268 N° 6 2021 págs. 2256 - 2258
  • Autores: Sola Sevilla, Noemí; Ricobaraza Abarquero, Ana; Hernández Alcoceba, Rubén; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN 1422-0067 Vol.22 N° 6 2021 págs. 3107
    Resumen
    Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our results show that the specific overexpression of this isoform does not induce significant behavioral or molecular effects at short or long term in the control strain. Only a tendency towards a worsening in the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together with a significant increase in the pro-inflammatory cytokine Il-1 beta. These results suggest that the age-related increase of SIRT2.3 found in the brain is not responsible for induction or prevention of senescence. Nevertheless, in combination with other risk factors, it could contribute to the progression of age-related processes. Understanding the specific role of SIRT2 on aging and the underlying molecular mechanisms is essential to design new and more successful therapies for the treatment of age-related diseases.
  • Autores: Pereira Sánchez, Víctor (Autor de correspondencia); Franco, A. R.; de Castro Manglano, María Pilar; et al.
    Revista: FRONTIERS IN PSYCHIATRY
    ISSN 1664-0640 Vol.12 2021 págs. 759696
    Resumen
    Neuroimaging research seeks to identify biomarkers to improve the diagnosis, prognosis, and treatment of attention-deficit/hyperactivity disorder (ADHD), although clinical translation of findings remains distant. Resting-state functional magnetic resonance imaging (R-fMRI) is increasingly being used to characterize functional connectivity in the brain. Despite mixed results to date and multiple methodological challenges, dominant hypotheses implicate hyperconnectivity across brain networks in patients with ADHD, which could be the target of pharmacological treatments. We describe the experience and results of the Clinica Universidad de Navarra (Spain) Metilfenidato (CUNMET) pilot study. CUNMET tested the feasibility of identifying R-fMRI markers of clinical response in children with ADHD undergoing naturalistical pharmacological treatments. We analyzed cross-sectional data from 56 patients with ADHD (18 treated with methylphenidate, 18 treated with lisdexamfetamine, and 20 treatment-naive patients). Standard preprocessing and statistical analyses with attention to control for head motion and correction for multiple comparisons were performed. The only results that survived correction were noted in contrasts of children who responded clinically to lisdexamfetamine after long-term treatment vs. treatment-naive patients. In these children, we observed stronger negative correlations (anticorrelations) across nodes in six brain networks, which is consistent with higher across-network functional segregation in patients treated with lisdexamfetamine, i.e., less inter-network interference than in treatment-naive patients. We also note the lessons learned, which could help those pursuing clinically relevant multidisciplinary research in ADHD en route to eventual personalized medicine. To advance reproducible open science, our report is accompanied with links providing access to our data and analytic scripts.
  • Autores: Frederiksen, K. S. (Autor de correspondencia); Nielsen, T. R. ; Appollonio, I. ; et al.
    Revista: INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY
    ISSN 0885-6230 Vol.36 N° 2 2021 págs. 324 - 333
    Resumen
    Objectives Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. Methods An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. Results The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. Conclusions The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.
  • Autores: Belloch Perez, Francisco de Borja; Beltrán de Miguel, Elena; Venzala Bascoy, Elisabet; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN 0924-977X Vol.44 2021 págs. 51 - 65
    Resumen
    Circadian rhythms disturbance is widely observable in patients with major depression (MD) and is also associated with depression vulnerability. Of them, disturbed melatonin secretion rhythm is particularly relevant to MD and is strongly phase-locked to core body temperature (CBT) rhythm. Here we aim to study the specific role of each melatonin receptor (MT1 and MT2) subtype in melatonin regulation of circadian CBT and its possible relationship with depressive-like behaviors. MT1-/-, MT2-/- and WT (C57BL/6) mice were used. Anhedonia, using the sucrose intake test, circadian CBT, environmental place preference (EPP) conditioning and vulnerability to chronic social defeat stress (CSDS) procedure were studied. Moreover, the antidepressant effects of reboxetine (15 mg/kg/day, i.p.) for three weeks or ketamine (15 mg/kg i.p. every four days, 4 doses in total) were studied. Further, exposure to ultra-mild stress induced by individual housing for several weeks was also studied in these mice. MT2-/- mice showed anhedonia and lower CBT compared to WT and MT1-/-. In addition, while reward exposure raised nocturnal CBT in WT this increase did not take place in MT2-/- mice. Further, MT2-/- mice showed an enhanced vulnerability to stress-induced anhedonia and social avoidance as well as an impaired acquisition of novelty seeking behavior. Both reboxetine and ketamine reverted anhedonia and induced a clear anti-helpless behavior in the tail suspension test (TST). Reboxetine raised CBT in mice and reverted ultra-mild stress-induced anhedonia. Our findings show a primary role for MT2 receptors in the regulation of circadian CBT as well as anhedonia and suggest that these receptors could be involved in depressive disorders associated to disturbed melatonin function. (C) 2021 Elsevier B.V. and ECNP. All rights reserved.
  • Autores: Gulfo, J.; Pérez de San Román, J.; Ledda, A.; et al.
    Revista: PLOS ONE
    ISSN 1932-6203 Vol.16 N° 2 2021 págs. e0246930
    Resumen
    Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg(-/-) mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11 beta-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg(-/-) mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3 beta and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies.
  • Autores: Solas Zubiaurre, Maite; Van Dam, D.; Janssens, J.; et al.
    Revista: NEUROCHEMISTRY INTERNATIONAL
    ISSN 0197-0186 Vol.150 2021 págs. 105185
    Resumen
    Even though the involvement of serotonin (5-hydroxytryptamine; 5-HT) and its receptors in Alzheimer's disease (AD) is widely accepted, data on the expression and the role of 5-HT7 receptors in AD is relatively limited. Therefore, the objective of the present work was to study the expression of serotonergic 5-HT7 receptors in postmortem samples of AD brains and correlate it with neurotransmitter levels, cognition and behavior. The study population consisted of clinically well-characterized and neuropathologically confirmed AD patients (n = 42) and age-matched control subjects (n = 18). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and high-performance liquid chromatography were performed on Brodmann area (BA) 7, BA10, BA22, BA24, hippocampus, amygdala, thalamus and cerebellum to measure mRNA levels of 5-HT7 receptors (HTR7), as well as the concentrations of various monoamine neurotransmitters and their metabolites. Decreased levels of HTR7 mRNA were observed in BA10. A significant association was observed between HTR7 levels in BA10 and BEHAVE-AD cluster B (hallucinations) (rs(28) = 0.444, P < 0.05). In addition, a negative correlation was observed between HTR7 levels in BA10 and both MHPG concentrations in this brain region (rs(45) = -0.311; P < 0.05), and DOPAC levels in the amygdala (rs(42) = -0.311; P < 0.05). Quite surprisingly, no association was found between HTR7 levels and cognitive status. Altogether, this study supports the notion of the involvement of 5-HT7 receptors in psychotic symptoms in AD, suggesting the interest of testing antagonist acting at this receptor to specifically treat psychotic symptoms in this illness.
  • Autores: Fernández Matarrubia, Marta (Autor de correspondencia); Goñi Mateos, Leticia; Rognoni Trueba, María Teresa; et al.
    Revista: JOURNAL OF ALZHEIMERS DISEASE
    ISSN 1387-2877 Vol.79 N° 3 2021 págs. 1257 - 1268
    Resumen
    Background: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive. Objective: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort. Methods: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype. Results: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE epsilon 4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score beta = 0.76 95%CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 beta = 0.63; 95%CI -0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE epsilon 4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p = 0.039 for LTPA). Conclusion: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE epsilon 4 non-carriers.
  • Autores: Loera-Valencia, R. (Autor de correspondencia); Ismail, M. A. M.; Goikolea, J.; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN 0893-7648 Vol.58 N° 12 2021 págs. 6063 - 6076
    Resumen
    Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer's disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown. We used a high-fat/high-cholesterol diet in mice to study the effects of hypercholesterolemia over the alarmin S100A8 cascade in the hippocampus. Using CYP27Tg, a transgenic mouse model, we show that the hypercholesterolemia influence on the brain is mediated by the excess of 27-hydroxycholesterol (27-OH), a cholesterol metabolite. We also employed an acute model of 27-OH intraventricular injection in the brain to study RAGE and S100A8 response. We used primary cultures of neurons and astrocytes to study the effect of high levels of 27-OH over the S100A8 alarmin cascade. We report that a high-fat/high-cholesterol diet leads to an increase in S100A8 production in the brain. In CYP27Tg, we report an increase of S100A8 and its receptor RAGE in the hippocampus under elevated 27-OH in the brain. Using siRNA, we found that 27-OH upregulation of RAGE in astrocytes and neurons is mediated by the nuclear receptor RXR gamma. Silencing RXR gamma in neurons prevented 27-OH-mediated upregulation of RAGE. These results show that S100A8 alarmin and RAGE respond to high levels of 27-OH in the brain in both neurons and astrocytes through RXR gamma. Our study supports the notion that 27-OH mediates detrimental effects of hypercholesterolemia to the brain via alarmin signaling.
  • Autores: Janeiro Arenas, Manuel Humberto; García Ardanaz, Carlos; Sola Sevilla, Noemí; et al.
    Revista: ADVANCES IN LABORATORY MEDICINE / AVANCES EN MEDICINA DE LABORATORIO
    ISSN 2628-491X Vol.2 N° 1 2021 págs. 39 - 50
    Resumen
    Objetivos: La enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa. La EA es la principal causa de demencia en el mundo, siendo el envejecimiento el principal factor de riesgo. Los criterios diagnósticos para la enfermedad de Alzheimer suelen basarse en datos clínicos. No obstante, es necesario establecer una definición biológica de la enfermedad de Alzheimer basada en biomarcadores que reflejen la neuropatología subyacente. Contenido: El objetivo de esta revisión es presentar los resultados obtenidos en la medición de biomarcadores nuevos y ya conocidos en los fluidos biológicos o en neuroimágenes. Resumen: Actualmente se emplean tres biomarcadores para el diagnóstico de la enfermedad de Alzheimer_Aß42, t-Tau y p-Tau. El uso diagnóstico de biomarcadores en el líquido cefalorraquídeo (LCR) presenta algunas limitaciones debido a que la obtención invasiva mediante punción lumbar puede provocar efectos secundarios. La práctica más común en los centros clínicos es la medición en plasma o suero, ya que es mínimamenteinvasiva y, en consecuencia, se puede obtener y procesar con mayor facilidad. Las dos principales proteínas implicadas en el proceso patológico, Aß y Tau, se pueden visualizar empleando técnicas de neuroimagen como la PET. ¿ Perspectivas: Dado que está ampliamente aceptado que la enfermedad de Alzheimer comienza décadas antes de que se ¿ diagnostiquen los primeros síntomas clínicos, la detección de alteraciones biológicas previa a la aparición de la sintomatología clínica permitiría su diagnóstico precoz o incluso abriría la puerta a nuevas opciones terapéuticas.
  • Autores: Cuadrado Tejedor, María del Mar (Autor de correspondencia); Pérez González, Marta; Alfaro-Ruiz, R.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN 1661-6596 Vol.22 N° 21 2021 págs. 11950
    Resumen
    Despite the well-accepted role of the two main neuropathological markers (beta-amyloid and tau) in the progression of Alzheimer's disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.
  • Autores: Pérez González, Marta; Badesso, Sara; Lorenzo Ramos, María Elena; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN 1422-0067 Vol.22 N° 17 2021 págs. 9120
    Resumen
    Understanding the mechanisms involved in cognitive resilience in Alzheimer's disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. In the present study, we performed a transcriptomic analysis using the prefrontal cortex of demented and resilient Tg2576 transgenic AD mice. We have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function, and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, CD4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed CD4 expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. These findings highlight the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4(+) cells in the brain as a key player of cognitive dysfunction in AD.
  • Autores: Cortés Erice, María; Fernández, R.; Cuesta, M.; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN 0924-977X Vol.53 N° Supplement 1 2021 págs. S271 - S272
  • Autores: García Ardanaz, Carlos; Ramírez Gil, María Javier; Smerdou Picazo, Cristian; et al.
    Revista: GLIA
    ISSN 0894-1491 Vol.69 2021 págs. E232 - E233
  • Autores: Galiano, A.; Mengual Poza, Elisa; García de Eulate Ruiz, María Reyes; et al.
    Revista: BRAIN IMAGING AND BEHAVIOR
    ISSN 1931-7557 Vol.14 N° 2 2020 págs. 436 - 450
    Resumen
    Aging leads to cerebral perfusion and functional connectivity changes that have been assessed using various neuroimaging techniques. In addition, a link between these two parameters has been demonstrated in healthy young adults. In this work, we employed arterial spin labeling (ASL) fMRI to measure global and voxel-wise differences in cerebral blood flow (CBF) and intrinsic connectivity contrast (ICC) in the resting state in a group of cognitively normal elderly subjects and a group of cognitively normal young subjects, in order to assess the effects of aging on CBF-ICC coupling, which had not been previously evaluated. Our results showed age-related global and regional CBF decreases in prefrontal mesial areas, lateral frontal regions, insular cortex, lateral parietal areas, precuneus and occipital regions. Subcortically, perfusion was reduced in the medial thalamus and caudate nucleus. ICC was also found reduced with age in prefrontal cortical areas and insular cortex, affecting key nodes of the default mode and salience networks. Areas of ICC and CBF decrease partially overlapped, however, the CBF reduction was more extensive and encompassed more areas. This dissociation was accompanied by a decrease in CBF-ICC coupling. These results suggest that aging leads to a disruption in the relationship between CBF and intrinsic functional connectivity that could be due to neurovascular dysregulation.
  • Autores: Pérez González, Marta; Mendioroz, M.; Badesso, Sara; et al.
    Revista: PROGRESS IN NEUROBIOLOGY
    ISSN 0301-0082 Vol.191 2020 págs. 101818
    Resumen
    Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer's disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/ PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits.
  • Autores: Díaz Perdigón, Teresa; Belloch Perez, Francisco de Borja; Ricobaraza Abarquero, Ana; et al.
    Revista: NEUROPSYCHOPHARMACOLOGY
    ISSN 1740-634X Vol.45 N° 2 2020 págs. 347-357
    Resumen
    The senescence-accelerated mouse prone-8 (SAMP8) model has been considered as a good model for aged-related cognitive decline and Alzheimer's disease (AD). Since epigenetic alterations represent a crucial mechanism during aging, in the present study we tested whether the inhibition of the histone deacetylase sirtuin 2 (SIRT2) could ameliorate the age-dependent cognitive impairments and associated neuropathology shown by SAMP8 mice. To this end, the potent SIRT2-selective inhibitor, 33i (5 mg/kg i. p. 8 weeks) was administered to 5-month-old (early treatment) and 8-month-old (late treatment) SAMP8 and aged matched control, senescence-accelerated mouse resistant-1 (SAMR1) mice. 33i administration to 5-month-old SAMP8 mice improved spatial learning and memory impairments shown by this strain in the Morris water maze. SAMP8 showed hyperphosphorylation of tau protein and decrease levels of SIRT1 in the hippocampus, which were not altered by 33i treatment. However, this treatment upregulated the glutamate receptor subunits GluN2A, GluN2B, and GluA1 in both SAMR1 and SAMP8. Moreover, early SIRT2 inhibition prevented neuroinflammation evidenced by reduced levels of GFAP, IL-1 beta, Il-6, and Tnf-alpha, providing a plausible explanation for the improvement of cognitive deficits shown by 33i-treated SAMP8 mice. When 33i was administered to 8-month-old SAMP8 with a severe established pathology, increases in GluN2A, GluN2B, and GluA1 were observed; however, it was not able to reverse the
  • Autores: Gil Iturbe, Eva; Solas Zubiaurre, Maite; Cuadrado Tejedor, María del Mar; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN 0893-7648 Vol.57 N° 2 2020 págs. 798 - 805
    Resumen
    The brain depends on glucose as a source of energy. This implies the presence of glucose transporters, being GLUT1 and GLUT3 the most relevant. Expression of GLUT12 is found in mouse and human brain at low levels. We previously demonstrated GLUT12 upregulation in the frontal cortex of aged subjects that was even higher in aged Alzheimer's disease (AD) patients. However, the cause and the mechanism through which this increase occurs are still unknown. Here, we aimed to investigate whether the upregulation of GLUT12 in AD is related with aging or A beta deposition in comparison with GLUT1, GLUT3, and GLUT4. In the frontal cortex of two amyloidogenic mouse models (Tg2576 and APP/PS1) GLUT12 levels were increased. Contrary, expression of GLUT1 and GLUT3 were decreased, while GLUT4 did not change. In aged mice and the senescence-accelerated model SAMP8, GLUT12 and GLUT4 were upregulated in comparison with young animals. GLUT1 and GLUT3 did not show significant changes with age. The effect of beta-amyloid (A beta) deposition was also evaluated in A beta peptide i.c.v. injected mice. In the hippocampus, GLUT12 expression increased whereas GLUT4 was not modified. Consistent with the results in the amyloidogenic models, GLUT3 and GLUT1 were downregulated. In summary, A beta increases GLUT12 protein expression in the brain pointing out a central role of the transporter in AD pathology and opening new perspectives for the treatment of this neurodegenerative disease.
  • Autores: Masmudi-Martin, M. ; Navarro-Lobato, I. ; Lopez-Aranda, M. F.; et al.
    Revista: NEUROSCIENCE
    ISSN 0306-4522 Vol.448 2020 págs. 287 - 298
    Resumen
    The integrity of the perirhinal cortex (PRh) is essential for object recognition memory (ORM) function, and damage to this brain area in animals and humans induces irreversible ORM deficits. Here, we show that activation of area V2, a brain area interconnected with brain circuits of ventral stream and medial temporal lobe that sustain ORM, by expression of regulator of G-protein signaling 14 of 414 amino acids (RGS14(414)) restored ORM in memory-deficient PRh-lesioned rats and nonhuman primates. Furthermore, this treatment was sufficient for full recovery of ORM in rodent models of aging and Alzheimer's disease, conditions thought to affect multiple brain areas. Thus, RGS14(414)-mediated activation of area V2 has therapeutic relevance in the recovery of recognition memory, a type of memory that is primarily affected in patients or individuals with symptoms of memory dysfunction. These findings suggest that area V2 modulates the processing of memory-related information through activation of interconnected brain circuits formed by the participation of distinct brain areas. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Autores: Lachen-Montes, M. ; Mendizuri, N. ; Ausin, K. ; et al.
    Revista: JOURNAL OF PROTEOME RESEARCH
    ISSN 1535-3893 Vol.19 N° 12 2020 págs. 4826 - 4843
    Resumen
    The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer's disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1(-/-) mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHDI is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634.
  • Autores: Janeiro Arenas, Manuel Humberto; Orbe Lopategui, Josune; Solas Zubiaurre, Maite; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN 0924-977X Vol.40 2020 págs. S434 - S435
  • Autores: Puerta Ruiz de Azua, Elena; Tordera Baviera, Rosa María; Beltran, E.; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN 0924-977X Vol.40 2020 págs. S46 - S47
  • Autores: Ambrosio Gutierrez, Leire; Portillo Vega, María Carmen; Martín Lanas, Raquel; et al.
    Revista: MOVEMENT DISORDERS
    ISSN 0885-3185 Vol.35 N° S1 2020 págs. S575 - S576
  • Autores: Cortés Erice, María; Fernandez, R. ; Cuesta, M. ; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN 0924-977X Vol.40 2020 págs. S201 - S202
  • Autores: Ortega-Suero, G.; Fernández Matarrubia, Marta; López-Valdés, E.; et al.
    Revista: ACS PHOTONICS
    ISSN 2330-4022 Vol.6 N° 2 2019 págs. 171 - 173
  • Autores: Matrov, D.; Kaart, T. ; Lanfumey, L.; et al.
    Revista: BEHAVIOURAL BRAIN RESEARCH
    ISSN 0166-4328 Vol.356 2019 págs. 435 - 443
    Resumen
    The psychopathology of depression is highly complex and the outcome of studies on animal models is divergent. In order to find brain regions that could be metabolically distinctively active across a variety of mouse depression models and to compare the interconnectivity of brain regions of wild-type and such genetically modified mice, histochemical mapping of oxidative metabolism was performed by the measurement of cytochrome oxidase activity. We included mice with the heterozygous knockout of the vesicular glutamate transporter (VGLUT(1)(-/+)), full knockout of the cannabinoid 1 receptor (CB1(-/-)), an anti-sense knockdown of the gluco- corticoid receptor (GRi) and overexpression of the human 5-hydroxytryptamine transporter (h5-HTT). Altogether 76 mouse brains were studied to measure oxidative metabolism in one hundred brain regions, and the obtained dataset was submitted to a variety of machine learning algorithms and multidimensional scaling. Overall, the top brain regions having the largest contribution to classification into depression model were the lateroanterior hypothalamic nucleus, the anterior part of the basomedial amygdaloid nucleus, claustrum, the suprachiasmatic nucleus, the ventromedial hypothalamic nucleus, and the anterior hypothalamic area. In terms of the patterns of inter-regional relationship between wild-type and genetically modified mice there was little overall difference, while the most deviating brain regions were cortical amygdala and ventrolateral and ventral posteromedial thalamic nuclei. The GRi mice that most clearly differed from their controls exhibited deviation of connectivity for a number of brain regions, such as ventrolateral thalamic nucleus, the intermediate part of the lateral septal nucleus, the anteriodorsal part of the medial amygdaloid nucleus, the medial division of the central amygdaloid nucleus, ventral pallidum, nucleus of the vertical limb of the diagonal band, anteroventral parts of the thalamic nucleus and parts of the bed nucleus of the stria terminalis. Conclusively, the GRi mouse model was characterized by changes in the functional connectivity of the extended amygdala and stress response circuits.
  • Autores: Vela, S.; Sáinz Amillo, Neira; Moreno Aliaga, María Jesús; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN 0893-7648 Vol.56 N° 3 2019 págs. 1618 - 1627
    Resumen
    A potential role of marine n-3 polyunsaturated fatty acids (-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, -3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of -3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.
  • Autores: Rabal, O. (Autor de correspondencia); Sanchez-Arias, J. A.; Cuadrado Tejedor, María del Mar; et al.
    Revista: ACS CHEMICAL NEUROSCIENCE
    ISSN 1948-7193 Vol.10 N° 9 2019 págs. 4076 - 4101
    Resumen
    Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).
  • Autores: Cuadrado Tejedor, María del Mar; Pérez González, Marta; Garcia-Munoz, C. ; et al.
    Revista: FRONTIERS IN AGING NEUROSCIENCE
    ISSN 1663-4365 Vol.11 2019 págs. 149
    Resumen
    The discouraging results with therapies for Alzheimer's disease (AD) in clinical trials, highlights the urgent need to adopt new approaches. Like other complex diseases, it is becoming clear that AD therapies should focus on the simultaneous modulation of several targets implicated in the disease. Recently, using reference compounds and the first-in class CM-414, we demonstrated that the simultaneous inhibition of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore, CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695 ameliorates memory impairment and diminishes brain A beta although its therapeutic effect was no longer apparent 4 weeks after the treatment was interrupted. An increase in the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70 (Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic treatment with CM-695 appears to reverse the AD phenotype in a safe and effective manner. Taking into account that AD is a multifactorial disorder, the multimodal action of these compounds and the different events they affect may open new avenues to combat AD.
  • Autores: Raygene, M (Autor de correspondencia); Liefhebber, JM; García Osta, Ana María; et al.
    Revista: MOLECULAR THERAPY - NUCLEIC ACIDS
    ISSN 2162-2531 Vol.16 2019 págs. 26 - 37
  • Autores: Martínez Valbuena, Iván; Valentí Azcárate, Rafael; Amat-Villegas, I.; et al.
    Revista: ANNALS OF NEUROLOGY
    ISSN 0364-5134 Vol.86 N° 4 2019 págs. 539 - 551
    Resumen
    Objective Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and beta-amyloid (A beta) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. Methods We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined A beta and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or A beta interact with amylin in either the pancreas or brain of these subjects. Results Cytoplasmic tau and A beta protein deposits were detected in pancreatic beta cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with A beta and tau in both the pancreas and hippocampus. Interpretation The presence of both tau and A beta inclusions in pancreatic beta cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019
  • Autores: Rabal Gracia, María Obdulia; Sanchez-Arias, J. A.; Cuadrado Tejedor, María del Mar; et al.
    Revista: ACS CHEMICAL NEUROSCIENCE
    ISSN 1948-7193 Vol.10 N° 3 2019 págs. 1765 - 1782
    Resumen
    In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDES) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDES and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).
  • Autores: Colyn, L.; Venzala Bascoy, Elisabet; Marco Martínez, Sonia; et al.
    Revista: BEHAVIOURAL BRAIN RESEARCH
    ISSN 0166-4328 Vol.373 2019 págs. 112079
    Resumen
    Previous studies show that chronic stress induces synaptic structural alterations in brain regions involved in emotional processing such as the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Yet, these studies are based mainly in animal exposure to unpredictable stressors or to restraint stress. On the other hand, studies using the chronic social defeat stress (CSDS), a relevant model of depression based on social conflict, are lacking. Here we aim to study the acute (24 h after CSDS) and long-term (one month after CSDS) effects of CSDS on dendritic and synaptic structures in the PFC and BLA of C57BL/6 mice. Specifically, BLA and PFC dendritic spine densities as well as BLA arborisation were analysed. Subsequently, we investigate in these regions the synaptic response to a friendly (interaction with a same strain mouse) or a fearful (interaction with a dominant strain mouse) social stimulus. Spine densities of the apical dendrites from the PFC pyramidal neurons were decreased by CSDS in the long-term (one month after CSDS). In addition, CSDS increased BLA stellate neurons spine density in the short-term (24 h after CSDS) and dendritic arborisation in the long-term. Moreover, long-term CSDS mice exposed to a fearful stimulus experienced a marked social avoidance and showed a significant increase in the expression of the immature form of the brain derived neurotrophic factor (proBDNF) in the amygdala. Taken together these results suggest the existence of persistent neuronal adaptations in the PFC and BLA in socially defeated mice. Specifically, spine density retraction in the PFC and increased BLA dendritic arborisation could represent an adaptive structural change allowing rapid expression of synaptic markers in response to fearful experiences.
  • Autores: Lachen-Montes, M.; Gonzalez-Morales, A.; Palomino, M.; et al.
    Revista: FRONTIERS IN AGING NEUROSCIENCE
    ISSN 1663-4365 Vol.11 2019
    Resumen
    The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment, which is considered an early event in Alzheimer's disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by overproduction of human mutated amyloid precursor protein (APP) clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice with respect to wild-type (WT) mice. In contrast, Akt and MAPK kinase 4 (SEK1)/stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD subjects with different neuropathological grading. Taken together, our data reflect the early impact of mutated APP on the OB molecular homeostasis, highlighting the progressive modulation of specific signaling pathways during the olfactory amyloidogenic pathology.
  • Autores: Chincarini, A. (Autor de correspondencia); Peira, E.; Morbelli, S.; et al.
    Revista: NEUROIMAGE. CLINICAL
    ISSN 2213-1582 Vol.23 2019
    Resumen
    Background: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. Methods: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to F-18-florbetaben (53 subjects), F-18-flutemetamol (62 subjects), F-18-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. Conclusion: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale.
  • Autores: Garcia, R. G. R. ; Ortega, G.; Valdes, E. L.; et al.
    Revista: EUROPEAN JOURNAL OF NEUROLOGY
    ISSN 1351-5101 Vol.26 2019 págs. 847 - 847
  • Autores: Sendino Miguel, Teresa; Mugueta Uriaque, María del Carmen; Macias Conde, Monica; et al.
    Revista: CLINICA CHIMICA ACTA
    ISSN 0009-8981 Vol.493 N° Supl. 1 2019 págs. S414 - S415
  • Autores: Cortés Jiménez, Adriana; Solas Zubiaurre, Maite; Pejenaute Martínez de Lizarrondo, Álvaro; et al.
    Revista: FREE RADICAL BIOLOGY AND MEDICINE
    ISSN 0891-5849 Vol.139 N° S1 2019 págs. S17 - S17
  • Autores: Gil Iturbe, Eva; Solas Zubiaurre, Maite; Cuadrado Tejedor, María del Mar; et al.
    Revista: ACTA PHYSIOLOGICA
    ISSN 1748-1708 Vol.227 N° Supl. 718 2019 págs. 83 - 84
  • Autores: Ferrero Hidalgo, Hilda; Larráyoz Roldán, Ignacio Marcos; Gil Bea, Francisco Javier; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN 0893-7648 Vol.55 N° 12 2018 págs. 8799 - 8814
    Resumen
    Neurodegenerative diseases represent a heterogeneous group of disorders whose common characteristic is the progressive degeneration of neuronal structure and function. Although much knowledge has been accumulated on the pathophysiology of neurodegenerative diseases over the years, more efforts are needed to understand the processes that underlie these diseases and hence to propose new treatments. Adrenomedullin (AM) is a multifunctional peptide involved in vasodilation, hormone secretion, antimicrobial defense, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins that interfere with microtubule dynamics. Furthermore, AM may intervene in neuronal dysfunction through other mechanisms such as immune and inflammatory response, apoptosis, or calcium dyshomeostasis. Alterations in AM expression have been described in neurodegenerative processes such as Alzheimer's disease or vascular dementia. This review addresses the current state of knowledge on AM and its possible implication in neurodegenerative diseases.
  • Autores: Moreno Ajona, David (Autor de correspondencia); Irimia Sieira, Pablo; Fernández Matarrubia, Marta
    Revista: HEADACHE
    ISSN 0017-8748 Vol.58 N° 5 2018 págs. 746 - 749
    Resumen
    ObjectiveTo expand the differential diagnosis of headache and ophthalmoparesis by describing a case report in which anti-GQ1b was demonstrated to be the cause. BackgroundAnti-GQ1b antibody syndrome refers to a clinical spectrum of conditions that share common mechanisms and overlapping manifestations, including the Miller-Fisher syndrome, pharyngeal-cervical-brachial weakness, and Bickerstaff brainstem encephalitis. Rare atypical cases presenting as acute ophthalmoparesis (AO) without ataxia or areflexia have been described. Headache is a rare condition in these disorders. MethodsA 49-year-old woman with no history of headaches began experiencing an acute severe bilateral throbbing headache associated with nausea and photophobia. Five days later, she developed constant binocular horizontal diplopia. ResultsBilateral paresis of both sixth nerves was noted. Her ocular fundi, tendon reflexes, and other findings of the physical exam were normal. In addition, both a brain MRI performed with gadolinium and a lumbar puncture yielded normal results. Serum anti-GQ1b IgG was found to be positive. Her symptoms resolved completely following treatment with immunoglobulins (0.4 g/kg/day for 5 days). ConclusionsThis is the first reported case of AO related to anti-GQ1b antibodies presenting with headache as its initial symptom. The presence of anti-GQ1b antibodies should be determined in patients with headache and AO of unknown origin. Immunoglobulins could hasten the resolution of symptoms
  • Autores: Ferrero Hidalgo, Hilda; Larrayoz, I. M.; Martisová, Eva; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN 0893-7648 Vol.55 N° 6 2018 págs. 5177 - 5183
    Resumen
    Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.
  • Autores: Muñoz-Cobo Orosa, Irene; Erburu Calvo, Mercedes Micaela; Zwergel, C.; et al.
    Revista: PSYCHOPHARMACOLOGY
    ISSN 0033-3158 Vol.235 N° 10 2018 págs. 2831 - 2846
    Resumen
    Rationale Antidepressant action has been linked to increased synaptic plasticity in which epigenetic mechanisms such as histone posttranslational acetylation could be involved. Interestingly, the histone deacetylases HDAC5 and SIRT2 are oppositely regulated by stress and antidepressants in mice prefrontal cortex (PFC). Besides, the neuroblastoma SH-SY5Y line is an in vitro neuronal model reliable to study drug effects with clear advantages over animals. Objectives We aimed to characterize in vitro the role of HDAC5 and SIRT2 in antidepressant regulation of neuroplasticity. Methods SH-SY5Y cultures were incubated with imipramine, fluoxetine, and reboxetine (10 mu M, 2 and 24 h) as well as the selective HDAC5 (MC3822, 5 mu M, 24 h) or SIRT2 (33i, 5 mu M, 24 h) inhibitors. The regulation of the brain-derived neurotrophic factor (BDNF), the vesicular glutamate transporter 1 (VGLUT1), the acetylated histones 3 (AcH3) and 4 (AcH4), HDAC5, and SIRT2 was studied. Comparatively, the long-term effects of these antidepressants (21 days, i.p.) in the mice (C57BL6, 8 weeks) PFC were studied. Results Antidepressants increased both in vitro and in vivo expression of BDNF, VGLUT1, AcH3, and AcH4. Moreover, imipramine and reboxetine increased the phosphorylated form of HDAC5 (P-HDAC5), mediating its cytoplasmic export. Further, SIRT2 was downregulated by all antidepressants. Finally, specific inhibition of HDAC5 and SIRT2 increased neuroplasticity markers. Conclusions This study supports the validity of the SH-SY5Y model for studying epigenetic changes linked to synaptic plasticity induced by antidepressants as well as the effect of selective HDAC inhibitors. Particularly, nucleocytoplasmic export of HDAC5 and SIRT2 downregulation mediated by antidepressants could enhance synaptic plasticity markers leading to antidepressant action.
  • Autores: Rabal Gracia, María Obdulia; Sanchez-Arias, J. A.; Cuadrado Tejedor, María del Mar; et al.
    Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
    ISSN 0223-5234 Vol.150 2018 págs. 506 - 524
    Resumen
    We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo. (C) 2018 Elsevier Masson SAS. All rights reserved.
  • Autores: Zamarbide, M. (Autor de correspondencia); Gil Bea, Francisco Javier; Bannenberg, Paul; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN 2045-2322 Vol.8 2018
    Resumen
    The risk of suffering from Alzheimer's disease (AD) is higher in individuals from AD-affected mothers. The purpose of this investigation was to study whether maternal transmission might produce AD-related alterations in progenies of mice that do not have any genotypic alteration. We used cognitively-intact mothers harbouring in heterozygosity the transgene for overexpressing the Swedish double mutant version of the human amyloid precursor protein (hA(3PPswe). The phenotype of the offspring with or without the transgene resulting from crossing young Tg2576 females with wild-type males were compared with those of the offspring resulting from crossing wild-type females with Tg2576 males. The hAOPPswe-bearing offspring from Tg2576 mothers showed an aggravated AD-like phenotype. Remarkably, cognitive, immunohistochemica I and some biochemical features displayed by Tg2576 heterozygous mice were also found in wild-type animals generated from Tg2576 females. This suggests the existence of a maternal imprinting in the wild-type offspring that confers a greater facility to launch an AD-like neurodegenerative cascade. Such progeny, lacking any mutant amyloid precursor protein, constitutes a novel model to study maternal transmission of AD and, even more important, to discover early risk markers that predispose to the development of AD.
  • Autores: Ferrero Hidalgo, Hilda; Larráyoz Roldán, Ignacio Marcos; Solas Zubiaurre, Maite; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN 0893-7648 Vol.55 N° 12 2018 págs. 9328 - 9333
    Resumen
    Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer's disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total III-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption.

Proyectos desde 2018

  • Título: Utilidad clínica de GDF15 y FGF21 como biomarcadores de riesgo de diabetes tipo 2. Efecto del envejecimiento.
    Código de expediente: 58/2021
    Investigador principal: JAVIER GOMEZ AMBROSI.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2021 GN Proyectos de Investigación en salud
    Fecha de inicio: 23-12-2021
    Fecha fin: 22-12-2024
    Importe concedido: 79.925,00 €
    Fondos FEDER: SI
  • Título: Papel de SIRT2 microglial en la Enfermedad de Alzheimer
    Código de expediente: PID2020-119729GB-I00
    Investigador principal: ELENA PUERTA RUIZ DE AZUA.
    Financiador: AGENCIA ESTATAL DE INVESTIGACION
    Convocatoria: 2020 AEI PROYECTOS I+D+i (incluye Generación del conocimiento y Retos investigación)
    Fecha de inicio: 01-09-2021
    Fecha fin: 31-08-2024
    Importe concedido: 157.300,00 €
    Fondos FEDER: NO
  • Título: Desarrollo de terapias nasales inmunomoduladoras en envejecimiento y neurodegeneración (INNOLFACT)
    Código de expediente: 0011-1411-2020-000049
    Investigador principal: JUAN JOSE LASARTE SAGASTIBELZA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-11-2022
    Importe concedido: 399.103,16 €
    Fondos FEDER: NO
  • Título: INNOLFACT: Implementación de Medicina de Precisión Olfatoria y Desarrollo de terapias nasales
    Código de expediente: 0011-1411-2020-000036
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-11-2022
    Importe concedido: 601.228,00 €
    Fondos FEDER: NO
  • Título: Estudio de la función de PLA2G4E en plasticidad cerebral y en la resiliencia cognitiva. Nueva estrategia para el tratamiento de la enfermedad de Alzheimer
    Código de expediente: PID2019-104921RB-I00
    Investigador principal: ANA MARIA GARCIA OSTA, MARIA DEL MAR CUADRADO TEJEDOR.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2019 MCIU - AEI PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-06-2020
    Fecha fin: 31-05-2023
    Importe concedido: 108.900,00 €
    Fondos FEDER: SI
  • Título: Implicación de guanilina y uroguanilina en el desarrollo de obesidad y resistencia a la insulina.
    Código de expediente: PI19/00990
    Investigador principal: AMAIA RODRIGUEZ MURUETA-GOYENA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 171.820,00 €
    Fondos FEDER: SI
  • Título: Validación de los microRNAs plasmáticos como biomarcadores de la enfermedad de Alzheimer: estudio clínico, de neuroimagen y genética molecular.
    Código de expediente: 97/2018
    Investigador principal: MARTA FERNANDEZ MATARRUBIA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2018 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2019
    Fecha fin: 05-10-2021
    Importe concedido: 69.058,65 €
    Fondos FEDER: SI
  • Título: Estudio del eje p27-Cdk2 como nueva diana terapéutica para combatir la obesidad y el Alzheimer durante el envejecimiento
    Código de expediente: 0011-1383-2019-000006
    Investigador principal: ANA MARIA GARCIA OSTA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 21.808,75 €
    Fondos FEDER: NO
  • Título: Estudio del eje p27-Cdk2 como nueva diana terapéutica para combatir la obesidad y el Alzheimer durante el envejecimiento
    Código de expediente: 0011-1383-2019-00005 (PC056 ALZOBIN)
    Investigador principal: MARIA JESUS MORENO ALIAGA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 GN Centros
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 49.077,94 €
    Fondos FEDER: NO
  • Título: SinPARK. Identificación de patrones de neuroinflamación específicos en la muerte neuronal dependiente de alfa-sinucleína en modelos de enfermedad de Parkinson
    Código de expediente: 0011-1383-2019-000005 PC60
    Investigador principal: MARIA SOLEDAD AYMERICH SOLER.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 GN Centros
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 70.700,00 €
    Fondos FEDER: NO
  • Título: GENEURONA. Implantación del diagnóstico genómico de la epilepsia y la migraña en Navarra
    Código de expediente: 0011-1411-2018-000044
    Investigador principal: ANA MARIA GARCIA OSTA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018- GN PROY. ESTRATEGICOS DE I+D 2018-2020
    Fecha de inicio: 01-04-2018
    Fecha fin: 30-11-2020
    Importe concedido: 476.239,53 €
    Fondos FEDER: NO
  • Título: Redes cerebrales de procesamiento temporal en pacientes estables con esquizofrenia frente a trastorno bipolar
    Código de expediente: PI17/00240
    Investigador principal: FELIPE ORTUÑO SANCHEZ-PEDREÑO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-06-2022
    Importe concedido: 54.450,00 €
    Fondos FEDER: SI
  • Título: Modulación de la interacción neurona-glía a través del sistema endocannabinoide como estrategia de neuroprotección para la enfermedad de Parkinson
    Código de expediente: PI17/01931
    Investigador principal: MARIA SOLEDAD AYMERICH SOLER.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-12-2020
    Importe concedido: 99.220,00 €
    Fondos FEDER: SI
  • Título: Descifrando el papel del GLUT1 astrocítico en la enfermedad de Alzheimer.
    Código de expediente: SAF2017-87619-P
    Investigador principal: MAITE SOLAS ZUBIAURRE.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 MINECO EXCELENCIA
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-09-2022
    Importe concedido: 196.262,00 €
    Fondos FEDER: SI
  • Título: Inhibición de Sirtuina 2: una nueva estrategia terapéutica para el tratamiento de la Enfermedad de Alzheimer.
    Código de expediente: SAF2017-87595-R
    Investigador principal: ELENA PUERTA RUIZ DE AZUA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 MINECO RETOS INVESTIGACION. PROYECTOS DE I+D+i
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-09-2021
    Importe concedido: 142.659,00 €
    Fondos FEDER: SI
  • Título: Papel de HDAC5 y SIRT2 en el grado de severidad de la depresión y en la eficacia clínica de los antidepresivos en pacientes de Navarra
    Código de expediente: 81/2017
    Investigador principal: ROSA MARIA TORDERA BAVIERA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN SALUD
    Fecha de inicio: 16-12-2017
    Fecha fin: 31-12-2021
    Importe concedido: 90.000,00 €
    Fondos FEDER: NO
  • Título: Identificación de factores genéticos y epigeneticos que confieren resistencia al desarrollo de demencia
    Código de expediente: 67/2017
    Investigador principal: ANA MARIA GARCIA OSTA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2017 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 15-12-2017
    Fecha fin: 31-03-2021
    Importe concedido: 90.000,00 €
    Fondos FEDER: SI
  • Título: Estudio de la interacción de adipoquinas y mioquinas en el desarrollo de obesidad y comorbilidades asociadas.
    Código de expediente: PI16/00221
    Investigador principal: AMAIA RODRIGUEZ MURUETA-GOYENA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2016 AES PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 92.565,00 €
    Fondos FEDER: SI
  • Título: Evaluación del impacto de la imagen pet de Amiloide - beta en el diagnóstico y control clínico de los pacientes con deterioro cognitivo evaluados por sospecha de enfermedad de Alzheimer (EA)
    Código de expediente: DTS15/00141
    Investigador principal: JAVIER IGNACIO ARBIZU LOSTAO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2015 AES DESARROLLO TECNOLÓGICO EN SALUD
    Fecha de inicio: 01-01-2016
    Fecha fin: 31-12-2018
    Importe concedido: 59.139,00 €
    Fondos FEDER: NO
  • Título: Nueva estrategia para el tratamiento de la EA: validación de dianas epigenéticas, desde in-vitro a un modelo murino de la enfermedad. Diseño y desarrollo de nuevas herramientas farmacológicas
    Código de expediente: PI14/01244
    Investigador principal: ANA MARIA GARCIA OSTA, MARIA DEL MAR CUADRADO TEJEDOR.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2014 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2015
    Fecha fin: 30-12-2018
    Importe concedido: 104.665,00 €
    Fondos FEDER: SI
  • Título: Impact of astrocytic insulin receptor on cognitive deficiencies associated to neuropsychiatric disorders
    Código de expediente: 28177
    Investigador principal: MAITE SOLAS ZUBIAURRE
    Financiador: BRAIN & BEHAVIOUR RESEARCH FOUNDATION
    Convocatoria: NARSAD YOUNG INVESTIGATOR GRANT
    Fecha de inicio: 15-01-2020
    Fecha fin: 15-01-2022
    Importe concedido: 70.000,00 €
    Fondos FEDER: NO