Browsing by Keyword "Astrocitos"
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Publication Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming(Multidisciplinary Digital Publishing Institute (MDPI), 2021-06-11) Tovar, Rubén; Vargas, Antonio; Aranda, Jesús; Sánchez-Salido, Lourdes; González-González, Laura; Chowen, Julie A.; Rodríguez de Fonseca, Fernando; Suárez, Juan; Rivera, Patricia; [Tovar,R; Vargas,A; Aranda,J; Sánchez-Salido,L; González-González,L; Rodríguez de Fonseca,F; Suárez,J; Rivera,P] Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain. [Tovar,R; Vargas,A; Sánchez-Salido,L; Rodríguez de Fonseca,F; Rivera,P] UGC Salud Mental, Hospital Regional Universitario de Málaga, Málaga, Spain. [Tovar,R; Aranda,J] Andalucia Tech, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Chowen,JA] Department of Endocrinology, Instituto de Investigación Biomédica la Princesa, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Madrid, Spain. [Chowen,JA] CIBEROBN (Centro de Investigación Biomédica en Red Sobre Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain. [Chowen,JA] IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain. [Suárez,J] Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Universidad de Málaga, Málaga, Spain.Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.Publication Human Pluripotent Stem Cell-Derived Neural Cells as a Relevant Platform for Drug Screening in Alzheimer's Disease(Multidisciplinary Digital Publishing Institute (MDPI), 2020-09-18) Garcia-Leon, Juan Antonio; Caceres-Palomo, Laura; Sanchez-Mejias, Elisabeth; Mejias-Ortega, Marina; Nuñez-Diaz, Cristina; Fernandez-Valenzuela, Juan Jose; Sanchez-Varo, Raquel; Davila, Jose Carlos; Vitorica, Javier; Gutierrez, Antonia; [Garcia-Leon,JA; Caceres-Palomo,L; Sanchez-Mejias,E; Mejias-Ortega,M; Nuñez-Diaz,C; Fernandez-Valenzuela,JJ; Sanchez-Varo,R; Davila,JC; Gutierrez,A] Departamento Biologia Celular, Genetica y Fisiologia, Instituto de Investigacion Biomedica de Malaga-IBIMA, Facultad de Ciencias, Universidad de Malaga, Malaga, Spain. [Garcia-Leon,JA; Caceres-Palomo,L; Sanchez-Mejias,E; Mejias-Ortega,M; Nuñez-Diaz,C; Fernandez-Valenzuela,JJ; Sanchez-Varo,R; Davila,JC; Vitorica,J; Gutierrez,A] Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Vitorica,J] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain.Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tangles are prime features of Alzheimer's disease (AD). The pathology of AD is very complex and still not fully understood, since different neural cell types are involved in the disease. Although neuronal function is clearly deteriorated in AD patients, recently, an increasing number of evidences have pointed towards glial cell dysfunction as one of the main causative phenomena implicated in AD pathogenesis. The complex disease pathology together with the lack of reliable disease models have precluded the development of effective therapies able to counteract disease progression. The discovery and implementation of human pluripotent stem cell technology represents an important opportunity in this field, as this system allows the generation of patient-derived cells to be used for disease modeling and therapeutic target identification and as a platform to be employed in drug discovery programs. In this review, we discuss the current studies using human pluripotent stem cells focused on AD, providing convincing evidences that this system is an excellent opportunity to advance in the comprehension of AD pathology, which will be translated to the development of the still missing effective therapies.Publication Pharmacological blockade of the fatty acid amide hydrolase (FAAH) alters neural proliferation, apoptosis and gliosis in the rat hippocampus, hypothalamus and striatum in a negative energy context.(Frontiers Media, 2015-03-27) Rivera, Patricia; Bindila, Laura; Pastor, Antoni; Pérez-Martín, Margarita; Pavón, Francisco-Javier; Serrano, Antonia; de la Torre, Rafael; Lutz, Beat; Rodríguez de Fonseca, Fernando; Suárez, Juan; [Rivera,P; Pavón,FJ; Serrano,A; Rodríguez de Fonseca,F; Suárez,J] UGC Salud Mental, Instituto de Investigación Biomédica (IBIMA), Universidad de Málaga-Hospital Universitario Regional de Málaga, Málaga, Spain. [Rivera,P; Pavón,FJ; Serrano,A; de la Torre,R; Rodríguez de Fonseca,F; Suárez,J] CIBER OBN, Instituto de Salud Carlos III, Madrid, Spain. [Bindila,L, Lutz,B] Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany. [Pastor,A; de la Torre,R] Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Spain. [Pastor,A] Facultat de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain. [Pérez-Martín,M] Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica (IBIMA), Universidad de Málaga, Málaga, Spain. [de la Torre, R] Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra (CEXS-UPF), Barcelona, Spain.Endocannabinoids participate in the control of neurogenesis, neural cell death and gliosis. The pharmacological effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which limits the endocannabinoid degradation, was investigated in the present study. Cell proliferation (phospho-H3(+) or BrdU(+) cells) of the main adult neurogenic zones as well as apoptosis (cleaved caspase-3(+)), astroglia (GFAP(+)), and microglia (Iba1(+) cells) were analyzed in the hippocampus, hypothalamus and striatum of rats intraperitoneally treated with URB597 (0.3 mg/kg/day) at one dose/4-days resting or 5 doses (1 dose/day). Repeated URB597 treatment increased the plasma levels of the N-acylethanolamines oleoylethanolamide, palmitoylethanolamide and arachidonoylethanolamine, reduced the plasma levels of glucose, triglycerides and cholesterol, and induced a transitory body weight decrease. The hippocampi of repeated URB597-treated rats showed a reduced number of phospho-H3(+) and BrdU(+) subgranular cells as well as GFAP(+), Iba1(+) and cleaved caspase-3(+) cells, which was accompanied with decreased hippocampal expression of the cannabinoid CB1 receptor gene Cnr1 and Faah. In the hypothalami of these rats, the number of phospho-H3(+), GFAP(+) and 3-weeks-old BrdU(+) cells was specifically decreased. The reduced striatal expression of CB1 receptor in repeated URB597-treated rats was only associated with a reduced apoptosis. In contrast, the striatum of acute URB597-treated rats showed an increased number of subventricular proliferative, astroglial and apoptotic cells, which was accompanied with increased Faah expression. Main results indicated that FAAH inhibitor URB597 decreased neural proliferation, glia and apoptosis in a brain region-dependent manner, which were coupled to local changes in Faah and/or Cnr1 expression and a negative energy context.Publication Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice(BioMed Central (BMC), 2020-06-09) Larramona-Arcas, Raquel; González-Arias, Candela; Perea, Gertrudis; Gutiérrez, Antonia; Vitorica, Javier; García-Barrera, Tamara; Gómez-Ariza, José Luis; Pascua-Maestro, Raquel; Ganfornina, María Dolores; Kara, Eleanna; Hudry, Eloise; Martinez-Vicente, Marta; Vila, Miquel; Galea, Elena; Masgrau, Roser; [Larramona-Arcas,R; Vila,M; Galea,E; Masgrau,R] Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, and, Institut de Neurociències (INc), Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Catalonia, Spain. [González-Arias,C; Perea,G] Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. [Gutiérrez,A] Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomedica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Gutiérrez,A; Vitorica,J; Martinez-Vicente,M; Vila,M] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Vitorica,J] Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain. [García-Barrera,T; Gómez-Ariza,JL] Departamento de Química, Facultad de Ciencias Experimentales, Campus de El Carmen, Centro de Investigación en Recursos Naturales, Salud y Medio Ambiente (RENSMA), Universidad de Huelva, Huelva, Spain. [Pascua-Maestro,R; Ganfornina,MD] Departamento de Bioquímica y Biología Molecular y Fisiología, Instituto de Biología y Genética Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain. [Kara,E; Hudry,E] Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. [Kara,E] Present Address: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland. [Martinez-Vicente,M; Vila,M] Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain. [Vila,M; Galea,E] CREA, Passeig Lluís Companys 23, Barcelona, Catalonia, Spain.Background: The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer's disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+signaling in astrocytes. Methods: Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed. Results: We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes. Conclusions: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.Publication The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity(Ivyspring International Publisher, 2021-05-12) Lorenzo, Petra I.; Martin Vazquez, Eugenia; López-Noriega, Livia; Fuente-Martín, Esther; Mellado-Gil, José M.; Franco, Jaime M.; Cobo-Vuilleumier, Nadia; Guerrero Martínez, José A.; Romero-Zerbo, Silvana Y.; Perez-Cabello, Jesús A.; Rivero Canalejo, Sabrina; Campos-Caro, Antonio; Lachaud, Christian Claude; Crespo Barreda, Alejandra; Aguilar-Diosdado, Manuel; García Fuentes, Eduardo; Martin-Montalvo, Alejandro; Álvarez Dolado, Manuel; Martin, Franz; Rojo-Martinez, Gemma; Pozo, David; Bérmudez-Silva, Francisco J.; Comaills, Valentine; Reyes, José C.; Gauthier, Benoit R.; [Lorenzo,PI; Martin Vazquez,E; López-Noriega,L; Fuente-Martín,E; Mellado-Gil,JM; Franco,JM; Cobo-Vuilleumier,N; Guerrero Martínez,JA; Perez-Cabello,JA; Lachaud,CC; Crespo Barreda,A; Martin-Montalvo,A; Álvarez Dolado,M; Martin,F; Comaills,V; Reyes,JC; Gauthier,BR] Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain. [Romero-Zerbo,SY; Rojo-Martinez,G; Bérmudez-Silva,FJ] Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain. [Rivero Canalejo,S] Department of Normal and Pathological Histology and Cytology, University of Seville School of Medicine, Seville, Spain. University Hospital “Puerta del Mar”, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain. [Campos-Caro,A; Aguilar-Diosdado,M] Department of Normal and Pathological Histology and Cytology, University of Seville School of Medicine, Seville, Spain. 4. University Hospital “Puerta del Mar”, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain. [Aguilar-Diosdado,M] Endocrinology and Metabolism Department, University Hospital “Puerta del Mar”, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain. [García Fuentes,E] Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Spain. [Martín,F; Rojo-Martínez,G; Bérmudez-Silva,FJ; Gauthier,BR] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both in vitro and in vivo, paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus.