Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage

Autores
Durand, Daniela Elizabeth; Carniglia, Lila; Beauquis, Juan; Caruso, Carla Mariana; Saravia, Flavia Eugenia; Lasaga, Mercedes Isabel
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Amyloid precursor protein (APP) shedding yields the Alzheimer´s disease (AD)-related peptide amyloid B (AB) through beta- and gamma-secretase cleavage. Alternatively, alpha-secretase cleavage generates a soluble and neuroprotective fragment (sAPPalpha) while precludes the production of AB. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPalpha production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPalpha release from cultured astrocytes by inducing alpha-secretases expression, whereas it decreased beta-secretase levels. LY379268-induced increase of PPAR-gamma levels could be involved in the effect of the agonist on sAPPalpha release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes.
Fil: Durand, Daniela Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Carniglia, Lila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Beauquis, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Caruso, Carla Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Saravia, Flavia Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Lasaga, Mercedes Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Materia
Astrocytes
Metabotropic Glutamate Receptor 3
Amyloid Precursor Protein
Secretases
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/6590
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/6590
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavageDurand, Daniela ElizabethCarniglia, LilaBeauquis, JuanCaruso, Carla MarianaSaravia, Flavia EugeniaLasaga, Mercedes IsabelAstrocytesMetabotropic Glutamate Receptor 3Amyloid Precursor ProteinSecretaseshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Amyloid precursor protein (APP) shedding yields the Alzheimer´s disease (AD)-related peptide amyloid B (AB) through beta- and gamma-secretase cleavage. Alternatively, alpha-secretase cleavage generates a soluble and neuroprotective fragment (sAPPalpha) while precludes the production of AB. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPalpha production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPalpha release from cultured astrocytes by inducing alpha-secretases expression, whereas it decreased beta-secretase levels. LY379268-induced increase of PPAR-gamma levels could be involved in the effect of the agonist on sAPPalpha release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes.Fil: Durand, Daniela Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Carniglia, Lila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Beauquis, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Caruso, Carla Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Saravia, Flavia Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Lasaga, Mercedes Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaElsevier2013-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/zipapplication/pdfhttp://hdl.handle.net/11336/6590Durand, Daniela Elizabeth; Carniglia, Lila; Beauquis, Juan; Caruso, Carla Mariana; Saravia, Flavia Eugenia; et al.; Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage; Elsevier; Neuropharmacology; 79; 11-2013; 180-1890028-3908enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0028390813005613info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuropharm.2013.11.015info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:37:42Zoai:ri.conicet.gov.ar:11336/6590instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:37:43.115CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
title Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
spellingShingle Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
Durand, Daniela Elizabeth
Astrocytes
Metabotropic Glutamate Receptor 3
Amyloid Precursor Protein
Secretases
title_short Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
title_full Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
title_fullStr Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
title_full_unstemmed Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
title_sort Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
dc.creator.none.fl_str_mv Durand, Daniela Elizabeth
Carniglia, Lila
Beauquis, Juan
Caruso, Carla Mariana
Saravia, Flavia Eugenia
Lasaga, Mercedes Isabel
author Durand, Daniela Elizabeth
author_facet Durand, Daniela Elizabeth
Carniglia, Lila
Beauquis, Juan
Caruso, Carla Mariana
Saravia, Flavia Eugenia
Lasaga, Mercedes Isabel
author_role author
author2 Carniglia, Lila
Beauquis, Juan
Caruso, Carla Mariana
Saravia, Flavia Eugenia
Lasaga, Mercedes Isabel
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Astrocytes
Metabotropic Glutamate Receptor 3
Amyloid Precursor Protein
Secretases
topic Astrocytes
Metabotropic Glutamate Receptor 3
Amyloid Precursor Protein
Secretases
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Amyloid precursor protein (APP) shedding yields the Alzheimer´s disease (AD)-related peptide amyloid B (AB) through beta- and gamma-secretase cleavage. Alternatively, alpha-secretase cleavage generates a soluble and neuroprotective fragment (sAPPalpha) while precludes the production of AB. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPalpha production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPalpha release from cultured astrocytes by inducing alpha-secretases expression, whereas it decreased beta-secretase levels. LY379268-induced increase of PPAR-gamma levels could be involved in the effect of the agonist on sAPPalpha release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes.
Fil: Durand, Daniela Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Carniglia, Lila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Beauquis, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Caruso, Carla Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Saravia, Flavia Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Lasaga, Mercedes Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
description Amyloid precursor protein (APP) shedding yields the Alzheimer´s disease (AD)-related peptide amyloid B (AB) through beta- and gamma-secretase cleavage. Alternatively, alpha-secretase cleavage generates a soluble and neuroprotective fragment (sAPPalpha) while precludes the production of AB. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPalpha production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPalpha release from cultured astrocytes by inducing alpha-secretases expression, whereas it decreased beta-secretase levels. LY379268-induced increase of PPAR-gamma levels could be involved in the effect of the agonist on sAPPalpha release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes.
publishDate 2013
dc.date.none.fl_str_mv 2013-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/6590
Durand, Daniela Elizabeth; Carniglia, Lila; Beauquis, Juan; Caruso, Carla Mariana; Saravia, Flavia Eugenia; et al.; Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage; Elsevier; Neuropharmacology; 79; 11-2013; 180-189
0028-3908
url http://hdl.handle.net/11336/6590
identifier_str_mv Durand, Daniela Elizabeth; Carniglia, Lila; Beauquis, Juan; Caruso, Carla Mariana; Saravia, Flavia Eugenia; et al.; Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage; Elsevier; Neuropharmacology; 79; 11-2013; 180-189
0028-3908
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0028390813005613
info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuropharm.2013.11.015
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/zip
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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