Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease

Pins, Benoit de; Cifuentes Díaz, Carmen; Farah, Amel Thamila; López Molina, Laura; Montalban, Enrica; Sancho Balsells, Anna; López Sala, Anna; Ginés Padrós, Silvia; Delgado García, José M.; Alberch i Vié, Jordi, 1959-; Gruart i Massó, Agnès; Girault, Jean-Antoine; Giralt Torroella, Albert

Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease

It has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer's disease (AD), but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse m...

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Autores:	Pins, Benoit de, Cifuentes Díaz, Carmen, Farah, Amel Thamila, López Molina, Laura, Montalban, Enrica, Sancho Balsells, Anna, López Sala, Anna, Ginés Padrós, Silvia, Delgado García, José M., Alberch i Vié, Jordi, 1959-, Gruart i Massó, Agnès, Girault, Jean-Antoine, Giralt Torroella, Albert
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2019
País:	España
Institución:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:2445/160697
Acceso en línea:	https://hdl.handle.net/2445/160697
Access Level:	acceso abierto
Palabra clave:	Astròcits Models animals en la investigació Malaltia d'Alzheimer Astrocytes Animal models in research Alzheimer's disease

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spelling	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer diseasePins, Benoit deCifuentes Díaz, CarmenFarah, Amel ThamilaLópez Molina, LauraMontalban, EnricaSancho Balsells, AnnaLópez Sala, AnnaGinés Padrós, SilviaDelgado García, José M.Alberch i Vié, Jordi, 1959-Gruart i Massó, AgnèsGirault, Jean-AntoineGiralt Torroella, AlbertAstròcitsModels animals en la investigacióMalaltia d'AlzheimerAstrocytesAnimal models in researchAlzheimer's diseaseIt has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer's disease (AD), but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse model of AD (5xFAD) and used it as an internal sensor to administer BDNF conditionally and locally. We first demonstrate the relevance of BDNF release from astrocytes by evaluating the effects of coculturing WT neurons and BDNF-deficient astrocytes. Next, we crossed 5xFAD mice with pGFAP:BDNF mice (only males were used) to create 5xFAD mice that overexpress BDNF when and where astrogliosis is initiated (5xF:pGB mice). We evaluated the behavioral phenotype of these mice. We first found that BDNF from astrocytes is crucial for dendrite outgrowth and spine number in cultured WT neurons. Double-mutant 5xF:pGB mice displayed improvements in cognitive tasks compared with 5xFAD littermates. In these mice, there was a rescue of BDNF/TrkB downstream signaling activity associated with an improvement of dendritic spine density and morphology. Clusters of synaptic markers, PSD-95 and synaptophysin, were also recovered in 5xF:pGB compared with 5xFAD mice as well as the number of presynaptic vesicles at excitatory synapses. Additionally, experimentally evoked LTP in vivo was increased in 5xF:pGB mice. The beneficial effects of conditional BDNF production and local delivery at the location of active neuropathology highlight the potential to use endogenous biomarkers with early onset, such as astrogliosis, as regulators of neurotrophic therapy in AD.SIGNIFICANCE STATEMENT Recent evidence places astrocytes as pivotal players during synaptic plasticity and memory processes. In the present work, we first provide evidence that astrocytes are essential for neuronal morphology via BDNF release. We then crossed transgenic mice (5xFAD mice) with the transgenic pGFAP-BDNF mice, which express BDNF under the GFAP promoter. The resultant double-mutant mice 5xF:pGB mice displayed a full rescue of hippocampal BDNF loss and related signaling compared with 5xFAD mice and a significant and specific improvement in all the evaluated cognitive tasks. These improvements did not correlate with amelioration of β amyloid load or hippocampal adult neurogenesis rate but were accompanied by a dramatic recovery of structural and functional synaptic plasticity.The Society for Neuroscience2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion18 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/160697Articles publicats en revistes (Biomedicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1523/JNEUROSCI.2121-18.2019Journal of Neuroscience, 2019, vol. 39, num. 13, p. 2441-2458https://doi.org/10.1523/JNEUROSCI.2121-18.2019cc-by-nc-sa (c) Pins, Benoit de et al., 2019http://creativecommons.org/licenses/by-nc-sa/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1606972026-05-29T05:05:01Z
dc.title.none.fl_str_mv	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease
title	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease
spellingShingle	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease Pins, Benoit de Astròcits Models animals en la investigació Malaltia d'Alzheimer Astrocytes Animal models in research Alzheimer's disease
title_short	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease
title_full	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease
title_fullStr	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease
title_full_unstemmed	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease
title_sort	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease
dc.creator.none.fl_str_mv	Pins, Benoit de Cifuentes Díaz, Carmen Farah, Amel Thamila López Molina, Laura Montalban, Enrica Sancho Balsells, Anna López Sala, Anna Ginés Padrós, Silvia Delgado García, José M. Alberch i Vié, Jordi, 1959- Gruart i Massó, Agnès Girault, Jean-Antoine Giralt Torroella, Albert
author	Pins, Benoit de
author_facet	Pins, Benoit de Cifuentes Díaz, Carmen Farah, Amel Thamila López Molina, Laura Montalban, Enrica Sancho Balsells, Anna López Sala, Anna Ginés Padrós, Silvia Delgado García, José M. Alberch i Vié, Jordi, 1959- Gruart i Massó, Agnès Girault, Jean-Antoine Giralt Torroella, Albert
author_role	author
author2	Cifuentes Díaz, Carmen Farah, Amel Thamila López Molina, Laura Montalban, Enrica Sancho Balsells, Anna López Sala, Anna Ginés Padrós, Silvia Delgado García, José M. Alberch i Vié, Jordi, 1959- Gruart i Massó, Agnès Girault, Jean-Antoine Giralt Torroella, Albert
author2_role	author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Astròcits Models animals en la investigació Malaltia d'Alzheimer Astrocytes Animal models in research Alzheimer's disease
topic	Astròcits Models animals en la investigació Malaltia d'Alzheimer Astrocytes Animal models in research Alzheimer's disease
description	It has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer's disease (AD), but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse model of AD (5xFAD) and used it as an internal sensor to administer BDNF conditionally and locally. We first demonstrate the relevance of BDNF release from astrocytes by evaluating the effects of coculturing WT neurons and BDNF-deficient astrocytes. Next, we crossed 5xFAD mice with pGFAP:BDNF mice (only males were used) to create 5xFAD mice that overexpress BDNF when and where astrogliosis is initiated (5xF:pGB mice). We evaluated the behavioral phenotype of these mice. We first found that BDNF from astrocytes is crucial for dendrite outgrowth and spine number in cultured WT neurons. Double-mutant 5xF:pGB mice displayed improvements in cognitive tasks compared with 5xFAD littermates. In these mice, there was a rescue of BDNF/TrkB downstream signaling activity associated with an improvement of dendritic spine density and morphology. Clusters of synaptic markers, PSD-95 and synaptophysin, were also recovered in 5xF:pGB compared with 5xFAD mice as well as the number of presynaptic vesicles at excitatory synapses. Additionally, experimentally evoked LTP in vivo was increased in 5xF:pGB mice. The beneficial effects of conditional BDNF production and local delivery at the location of active neuropathology highlight the potential to use endogenous biomarkers with early onset, such as astrogliosis, as regulators of neurotrophic therapy in AD.SIGNIFICANCE STATEMENT Recent evidence places astrocytes as pivotal players during synaptic plasticity and memory processes. In the present work, we first provide evidence that astrocytes are essential for neuronal morphology via BDNF release. We then crossed transgenic mice (5xFAD mice) with the transgenic pGFAP-BDNF mice, which express BDNF under the GFAP promoter. The resultant double-mutant mice 5xF:pGB mice displayed a full rescue of hippocampal BDNF loss and related signaling compared with 5xFAD mice and a significant and specific improvement in all the evaluated cognitive tasks. These improvements did not correlate with amelioration of β amyloid load or hippocampal adult neurogenesis rate but were accompanied by a dramatic recovery of structural and functional synaptic plasticity.
publishDate	2019
dc.date.none.fl_str_mv	2019 2020 2020 2020
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/160697
url	https://hdl.handle.net/2445/160697
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1523/JNEUROSCI.2121-18.2019 Journal of Neuroscience, 2019, vol. 39, num. 13, p. 2441-2458 https://doi.org/10.1523/JNEUROSCI.2121-18.2019
dc.rights.none.fl_str_mv	cc-by-nc-sa (c) Pins, Benoit de et al., 2019 http://creativecommons.org/licenses/by-nc-sa/3.0/es info:eu-repo/semantics/openAccess
rights_invalid_str_mv	cc-by-nc-sa (c) Pins, Benoit de et al., 2019 http://creativecommons.org/licenses/by-nc-sa/3.0/es
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	18 p. application/pdf application/pdf
dc.publisher.none.fl_str_mv	The Society for Neuroscience
publisher.none.fl_str_mv	The Society for Neuroscience
dc.source.none.fl_str_mv	Articles publicats en revistes (Biomedicina) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease

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