Browsing by MeSH term "Gliosis"
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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 IIIG9 inhibition in adult ependymal cells changes adherens junctions structure and induces cellular detachment(Springer, 2021-09-17) Baeza, Victor; Cifuentes, Manuel; Martínez, Fernando; Ramírez, Eder; Nualart, Francisco; Ferrada, Luciano; Oviedo, María José; De Lima, Isabelle; Troncoso, Ninoschka; Saldivia, Natalia; Salazar, Katterine; [Baeza,V; Martínez,F; Ramírez,E; Nualart,F; Oviedo,MJ; De Lima,I; Troncoso,N; Saldivia,N; Salazar,K] Laboratory of Neurobiology and Stem Cells, NeuroCellT, Department of Cellular Biology, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile. [Nualart,F; Ferrada,L; Salazar,K] Faculty of Biological Sciences, Center for Advanced Microscopy CMA BIOBIO, University of Concepcion, Concepcion, Chile. [Cifuentes,M] Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Malaga, Spain. [Cifuentes,M] Andalusian Center for Nanomedicine and Biotechnology, BIONAND, Malaga, Spain. [Cifuentes,M] Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, Malaga, Spain.Ependymal cells have multiple apical cilia that line the ventricular surfaces and the central canal of spinal cord. In cancer, the loss of ependymal cell polarity promotes the formation of different types of tumors, such as supratentorial anaplastic ependymomas, which are highly aggressive in children. IIIG9 (PPP1R32) is a protein restricted to adult ependymal cells located in cilia and in the apical cytoplasm and has unknown function. In this work, we studied the expression and localization of IIIG9 in the adherens junctions (cadherin/β-catenin-positive junctions) of adult brain ependymal cells using confocal and transmission electron microscopy. Through in vivo loss-of-function studies, ependymal denudation (single-dose injection experiments of inhibitory adenovirus) was observed, inducing the formation of ependymal cells with a "balloon-like" morphology. These cells had reduced cadherin expression (and/or delocalization) and cleavage of the cell death marker caspase-3, with "cilia rigidity" morphology (probably vibrational beating activity) and ventriculomegaly occurring prior to these events. Finally, after performing continuous infusions of adenovirus for 14 days, we observed total cell denudation and reactive parenchymal astrogliosis. Our data confirmed that IIIG9 is essential for the maintenance of adherens junctions of polarized ependymal cells. Eventually, altered levels of this protein in ependymal cell differentiation may increase ventricular pathologies, such as hydrocephalus or neoplastic transformation.Publication Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study(Multidisciplinary Digital Publishing Institute (MDPI), 2021-10-12) Moreno-Gonzalez, Ines; Edwards III, George A.; Hasan, Omar; Gamez, Nazaret; Schulz, Jonathan E.; Fernandez-Valenzuela, Juan Jose; Gutierrez, Antonia; Soto, Claudio; Schulz, Paul E.; [Moreno-Gonzalez,I; Edwards III,GA; Hasan,O; Gamez,N; Schulz,JE; Soto,C; Schulz,PE] Department of Neurology, The University of Texas Health Science Center at Houston, Houston, USA. [Moreno-Gonzalez,I; Gamez,N; Fernandez-Valenzuela,JJ; Gutierrez,A] Department of Cell Biology, Instituto de Investigacion Biomedica de Malaga-IBIMA, Faculty of Sicences, University of Malaga, Malaga, Spain. [Moreno-Gonzalez,I; Fernandez-Valenzuela,JJ; Gutierrez,A] Networking Biomedical Research Center on Neurodegenerative Diseases (CIBERBED), Madrid, Spain.Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer's disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.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 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.