Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease

Neurotoxic effects of amyloid β peptides are mediated through deregulation of intracellular Ca2+ homeostasis and signaling, but relatively little is known about amyloid β modulation of Ca2+ homeostasis and its pathological influence on glia. Here, we found that amyloid β oligomers caused a cytoplasm...

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Autores: Alberdi Alfonso, Elena María, Wyssenbach Ibarra, Ane, Alberdi, María, Sánchez Gómez, María Victoria, Cavaliere, Fabio, Rodríguez, José J., Verkhratsky, Alexei, Matute Almau, Carlos José
Tipo de recurso: artículo
Fecha de publicación:2013
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/19621
Acceso en línea:http://hdl.handle.net/10810/19621
Access Level:acceso abierto
Palabra clave:medicine
neuroscience
neurobiology
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spelling Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's diseaseAlberdi Alfonso, Elena MaríaWyssenbach Ibarra, AneAlberdi, MaríaSánchez Gómez, María VictoriaCavaliere, FabioRodríguez, José J.Verkhratsky, AlexeiMatute Almau, Carlos JosémedicineneuroscienceneurobiologyNeurotoxic effects of amyloid β peptides are mediated through deregulation of intracellular Ca2+ homeostasis and signaling, but relatively little is known about amyloid β modulation of Ca2+ homeostasis and its pathological influence on glia. Here, we found that amyloid β oligomers caused a cytoplasmic Ca2+ increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER Ca2+ release. Furthermore, amyloid β peptides triggered increased expression of glial fibrillary acidic protein (GFAP), as well as oxidative and ER stress, as indicated by eIF2α phosphorylation and overexpression of chaperone GRP78. These effects were decreased by ryanodine and 2APB, inhibitors of ryanodine receptors and InsP3 receptors, respectively, in both primary cultured astrocytes and organotypic cultures of hippocampus and entorhinal cortex. Importantly, intracerebroventricular injection of amyloid β oligomers triggered overexpression of GFAP and GRP78 in astrocytes of the hippocampal dentate gyrus. These data were validated in a triple-transgenic mouse model of Alzheimer's disease (AD). Overexpression of GFAP and GRP78 in the hippocampal astrocytes correlated with the amyloid β oligomer load in 12-month-old mice, suggesting that this parameter drives astrocytic ER stress and astrogliosis in vivo. Together, these results provide evidence that amyloid β oligomers disrupt ER Ca2+ homeostasis, which induces ER stress that leads to astrogliosis; this mechanism may be relevant to AD pathophysiology.201620162013info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/19621reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttp://onlinelibrary.wiley.com/doi/10.1111/acel.12054/abstractinfo:eu-repo/semantics/openAccessoai:addi.ehu.eus:10810/196212026-06-18T09:23:17Z
dc.title.none.fl_str_mv Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
title Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
spellingShingle Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
Alberdi Alfonso, Elena María
medicine
neuroscience
neurobiology
title_short Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
title_full Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
title_fullStr Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
title_full_unstemmed Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
title_sort Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease
dc.creator.none.fl_str_mv Alberdi Alfonso, Elena María
Wyssenbach Ibarra, Ane
Alberdi, María
Sánchez Gómez, María Victoria
Cavaliere, Fabio
Rodríguez, José J.
Verkhratsky, Alexei
Matute Almau, Carlos José
author Alberdi Alfonso, Elena María
author_facet Alberdi Alfonso, Elena María
Wyssenbach Ibarra, Ane
Alberdi, María
Sánchez Gómez, María Victoria
Cavaliere, Fabio
Rodríguez, José J.
Verkhratsky, Alexei
Matute Almau, Carlos José
author_role author
author2 Wyssenbach Ibarra, Ane
Alberdi, María
Sánchez Gómez, María Victoria
Cavaliere, Fabio
Rodríguez, José J.
Verkhratsky, Alexei
Matute Almau, Carlos José
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv medicine
neuroscience
neurobiology
topic medicine
neuroscience
neurobiology
description Neurotoxic effects of amyloid β peptides are mediated through deregulation of intracellular Ca2+ homeostasis and signaling, but relatively little is known about amyloid β modulation of Ca2+ homeostasis and its pathological influence on glia. Here, we found that amyloid β oligomers caused a cytoplasmic Ca2+ increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER Ca2+ release. Furthermore, amyloid β peptides triggered increased expression of glial fibrillary acidic protein (GFAP), as well as oxidative and ER stress, as indicated by eIF2α phosphorylation and overexpression of chaperone GRP78. These effects were decreased by ryanodine and 2APB, inhibitors of ryanodine receptors and InsP3 receptors, respectively, in both primary cultured astrocytes and organotypic cultures of hippocampus and entorhinal cortex. Importantly, intracerebroventricular injection of amyloid β oligomers triggered overexpression of GFAP and GRP78 in astrocytes of the hippocampal dentate gyrus. These data were validated in a triple-transgenic mouse model of Alzheimer's disease (AD). Overexpression of GFAP and GRP78 in the hippocampal astrocytes correlated with the amyloid β oligomer load in 12-month-old mice, suggesting that this parameter drives astrocytic ER stress and astrogliosis in vivo. Together, these results provide evidence that amyloid β oligomers disrupt ER Ca2+ homeostasis, which induces ER stress that leads to astrogliosis; this mechanism may be relevant to AD pathophysiology.
publishDate 2013
dc.date.none.fl_str_mv 2013
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/19621
url http://hdl.handle.net/10810/19621
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://onlinelibrary.wiley.com/doi/10.1111/acel.12054/abstract
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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