title: Hippocampal Astrocyte Cultures from Adult and Aged Rats Reproduce Changes in Glial Functionality Observed in the Aging Brain.
abstract: Astrocytes are dynamic cells that maintain brain homeostasis, regulate neurotransmitter systems, and process synaptic information, energy metabolism, antioxidant defenses, and inflammatory response. Aging is a biological process that is closely associated with hippocampal astrocyte dysfunction. In this sense, we demonstrated that hippocampal astrocytes from adult and aged Wistar rats reproduce the glial functionality alterations observed in aging by evaluating several senescence, glutamatergic, oxidative and inflammatory parameters commonly associated with the aging process. Here, we show that the p21 senescence-associated gene and classical astrocyte markers, such as glial fibrillary acidic protein (GFAP), vimentin, and actin, changed their expressions in adult and aged astrocytes. Age-dependent changes were also observed in glutamate transporters (glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)) and glutamine synthetase immunolabeling and activity. Additionally, according to in vivo aging, astrocytes from adult and aged rats showed an increase in oxidative/nitrosative stress with mitochondrial dysfunction, an increase in RNA oxidation, NADPH oxidase (NOX) activity, superoxide levels, and inducible nitric oxide synthase (iNOS) expression levels. Changes in antioxidant defenses were also observed. Hippocampal astrocytes also displayed age-dependent inflammatory response with augmentation of proinflammatory cytokine levels, such as TNF-α, IL-1β, IL-6, IL-18, and messenger RNA (mRNA) levels of cyclo-oxygenase 2 (COX-2). Furthermore, these cells secrete neurotrophic factors, including glia-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B) protein, and transforming growth factor-β (TGF-β), which changed in an age-dependent manner. Classical signaling pathways associated with aging, such as nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NFκB), heme oxygenase-1 (HO-1), and p38 mitogen-activated protein kinase (MAPK), were also changed in adult and aged astrocytes and are probably related to the changes observed in senescence marker, glutamatergic metabolism, mitochondrial dysfunction, oxidative/nitrosative stress, antioxidant defenses, inflammatory response, and trophic factors release. Together, our results reinforce the role of hippocampal astrocytes as a target for understanding the mechanisms involved in aging and provide an innovative tool for studies of astrocyte roles in physiological and pathological aging brain.
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
authors.forename: Bruna
authors.initials: B
authors.lastname: Bellaver
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
authors.forename: Débora Guerini
authors.initials: DG
authors.lastname: Souza
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
authors.forename: Diogo Onofre
authors.initials: DO
authors.lastname: Souza
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil. andrequincozes@ufrgs.br.
authors.forename: André
authors.initials: A
authors.lastname: Quincozes-Santos
mesh_terms: D000818:Animals; D008297:Male; D000375:Aging / Q000502:physiology; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D016922:Cellular Senescence; D003071:Cognition; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D017208:Rats, Wistar; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D051267:NF-E2-Related Factor 2
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003598:Cytoskeletal Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005974:Glutamate-Ammonia Ligase; D016328:NF-kappa B; D009418:S100 Proteins; D051267:NF-E2-Related Factor 2
keywords: Adult and aged hippocampal astrocytes; Aging; Inflammatory response; Nrf2/NFκB pathways; Oxidative stress