Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition

Autores
Bartolome, Fernando; de la Cueva, Macarena; Pascual, Consuelo; Antequera, Desiree; Fernández Cabada, Tamara; Gil, Carmen; Martinez, Ana; Carro, Eva
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. Methods: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice. After 5 weeks of S14 treatment, we evaluated cognitive functions and brain tissues. We also assessed the effects of S14 on the Aβ-treated human neuroblastome SH-SY5Y cell line. Results: Targeting the cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway, S14 rescued cognitive decline by improving hippocampal neurogenesis in APP/PS1 transgenic mice. Additionally, S14 treatment reverted the Aβ-induced reduction in mitochondrial mass in APP/PS1 mice and in the human neuroblastoma SH-SY5Y cells co-exposed to Aβ. The restoration of the mitochondrial mass was found to be a dual effect of S14: a rescue of the mitochondrial biogenesis formerly slowed down by Aβ overload, and a reduction in the Aβ-increased mitochondrial clearance mechanism of mitophagy. Conclusions: Here, we show new therapeutic effects of the PDE7 inhibitor, confirming S14 as a potential therapeutic drug for AD.
Fil: Bartolome, Fernando. Hospital 12 de Octubre; España. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España. Consejo Superior de Investigaciones Científicas; España
Fil: de la Cueva, Macarena. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; España
Fil: Pascual, Consuelo. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; España
Fil: Antequera, Desiree. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España
Fil: Fernández Cabada, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Superior de Investigaciones Científicas; España. Hospital 12 de Octubre; España
Fil: Gil, Carmen. Consejo Superior de Investigaciones Científicas; España
Fil: Martinez, Ana. Consejo Superior de Investigaciones Científicas; España
Fil: Carro, Eva. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España. Consejo Superior de Investigaciones Científicas; España
Materia
ALZHEIMER'S DISEASE
HIPPOCAMPUS
MEMORY
MITOCHONDRIA
MITOPHAGY
NEUROGENESIS
ORAL ADMINISTRATION
PHOSPHODIESTERASE
TRANSGENIC MICE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/100969
Acceder
id CONICETDig_1004745c1a76862a398697285ee3da52
oai_identifier_str oai:ri.conicet.gov.ar:11336/100969
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibitionBartolome, Fernandode la Cueva, MacarenaPascual, ConsueloAntequera, DesireeFernández Cabada, TamaraGil, CarmenMartinez, AnaCarro, EvaALZHEIMER'S DISEASEHIPPOCAMPUSMEMORYMITOCHONDRIAMITOPHAGYNEUROGENESISORAL ADMINISTRATIONPHOSPHODIESTERASETRANSGENIC MICEhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. Methods: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice. After 5 weeks of S14 treatment, we evaluated cognitive functions and brain tissues. We also assessed the effects of S14 on the Aβ-treated human neuroblastome SH-SY5Y cell line. Results: Targeting the cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway, S14 rescued cognitive decline by improving hippocampal neurogenesis in APP/PS1 transgenic mice. Additionally, S14 treatment reverted the Aβ-induced reduction in mitochondrial mass in APP/PS1 mice and in the human neuroblastoma SH-SY5Y cells co-exposed to Aβ. The restoration of the mitochondrial mass was found to be a dual effect of S14: a rescue of the mitochondrial biogenesis formerly slowed down by Aβ overload, and a reduction in the Aβ-increased mitochondrial clearance mechanism of mitophagy. Conclusions: Here, we show new therapeutic effects of the PDE7 inhibitor, confirming S14 as a potential therapeutic drug for AD.Fil: Bartolome, Fernando. Hospital 12 de Octubre; España. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España. Consejo Superior de Investigaciones Científicas; EspañaFil: de la Cueva, Macarena. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Pascual, Consuelo. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Antequera, Desiree. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; EspañaFil: Fernández Cabada, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Superior de Investigaciones Científicas; España. Hospital 12 de Octubre; EspañaFil: Gil, Carmen. Consejo Superior de Investigaciones Científicas; EspañaFil: Martinez, Ana. Consejo Superior de Investigaciones Científicas; EspañaFil: Carro, Eva. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España. Consejo Superior de Investigaciones Científicas; EspañaBioMed Central2018-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/100969Bartolome, Fernando; de la Cueva, Macarena; Pascual, Consuelo; Antequera, Desiree; Fernández Cabada, Tamara; et al.; Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition; BioMed Central; Alzheimer's Research and Therapy; 10; 1; 2-2018; 1-151758-9193CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://alzres.biomedcentral.com/articles/10.1186/s13195-018-0352-4info:eu-repo/semantics/altIdentifier/doi/10.1186/s13195-018-0352-4info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:06:13Zoai:ri.conicet.gov.ar:11336/100969instacron: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:34982025-10-22 11:06:13.809CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
title Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
spellingShingle Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
Bartolome, Fernando
ALZHEIMER'S DISEASE
HIPPOCAMPUS
MEMORY
MITOCHONDRIA
MITOPHAGY
NEUROGENESIS
ORAL ADMINISTRATION
PHOSPHODIESTERASE
TRANSGENIC MICE
title_short Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
title_full Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
title_fullStr Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
title_full_unstemmed Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
title_sort Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
dc.creator.none.fl_str_mv Bartolome, Fernando
de la Cueva, Macarena
Pascual, Consuelo
Antequera, Desiree
Fernández Cabada, Tamara
Gil, Carmen
Martinez, Ana
Carro, Eva
author Bartolome, Fernando
author_facet Bartolome, Fernando
de la Cueva, Macarena
Pascual, Consuelo
Antequera, Desiree
Fernández Cabada, Tamara
Gil, Carmen
Martinez, Ana
Carro, Eva
author_role author
author2 de la Cueva, Macarena
Pascual, Consuelo
Antequera, Desiree
Fernández Cabada, Tamara
Gil, Carmen
Martinez, Ana
Carro, Eva
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALZHEIMER'S DISEASE
HIPPOCAMPUS
MEMORY
MITOCHONDRIA
MITOPHAGY
NEUROGENESIS
ORAL ADMINISTRATION
PHOSPHODIESTERASE
TRANSGENIC MICE
topic ALZHEIMER'S DISEASE
HIPPOCAMPUS
MEMORY
MITOCHONDRIA
MITOPHAGY
NEUROGENESIS
ORAL ADMINISTRATION
PHOSPHODIESTERASE
TRANSGENIC MICE
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. Methods: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice. After 5 weeks of S14 treatment, we evaluated cognitive functions and brain tissues. We also assessed the effects of S14 on the Aβ-treated human neuroblastome SH-SY5Y cell line. Results: Targeting the cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway, S14 rescued cognitive decline by improving hippocampal neurogenesis in APP/PS1 transgenic mice. Additionally, S14 treatment reverted the Aβ-induced reduction in mitochondrial mass in APP/PS1 mice and in the human neuroblastoma SH-SY5Y cells co-exposed to Aβ. The restoration of the mitochondrial mass was found to be a dual effect of S14: a rescue of the mitochondrial biogenesis formerly slowed down by Aβ overload, and a reduction in the Aβ-increased mitochondrial clearance mechanism of mitophagy. Conclusions: Here, we show new therapeutic effects of the PDE7 inhibitor, confirming S14 as a potential therapeutic drug for AD.
Fil: Bartolome, Fernando. Hospital 12 de Octubre; España. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España. Consejo Superior de Investigaciones Científicas; España
Fil: de la Cueva, Macarena. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; España
Fil: Pascual, Consuelo. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; España
Fil: Antequera, Desiree. Hospital 12 de Octubre; España. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España
Fil: Fernández Cabada, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Superior de Investigaciones Científicas; España. Hospital 12 de Octubre; España
Fil: Gil, Carmen. Consejo Superior de Investigaciones Científicas; España
Fil: Martinez, Ana. Consejo Superior de Investigaciones Científicas; España
Fil: Carro, Eva. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas; España. Consejo Superior de Investigaciones Científicas; España
description Background: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. Methods: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice. After 5 weeks of S14 treatment, we evaluated cognitive functions and brain tissues. We also assessed the effects of S14 on the Aβ-treated human neuroblastome SH-SY5Y cell line. Results: Targeting the cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway, S14 rescued cognitive decline by improving hippocampal neurogenesis in APP/PS1 transgenic mice. Additionally, S14 treatment reverted the Aβ-induced reduction in mitochondrial mass in APP/PS1 mice and in the human neuroblastoma SH-SY5Y cells co-exposed to Aβ. The restoration of the mitochondrial mass was found to be a dual effect of S14: a rescue of the mitochondrial biogenesis formerly slowed down by Aβ overload, and a reduction in the Aβ-increased mitochondrial clearance mechanism of mitophagy. Conclusions: Here, we show new therapeutic effects of the PDE7 inhibitor, confirming S14 as a potential therapeutic drug for AD.
publishDate 2018
dc.date.none.fl_str_mv 2018-02
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/11336/100969
Bartolome, Fernando; de la Cueva, Macarena; Pascual, Consuelo; Antequera, Desiree; Fernández Cabada, Tamara; et al.; Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition; BioMed Central; Alzheimer's Research and Therapy; 10; 1; 2-2018; 1-15
1758-9193
CONICET Digital
CONICET
url http://hdl.handle.net/11336/100969
identifier_str_mv Bartolome, Fernando; de la Cueva, Macarena; Pascual, Consuelo; Antequera, Desiree; Fernández Cabada, Tamara; et al.; Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition; BioMed Central; Alzheimer's Research and Therapy; 10; 1; 2-2018; 1-15
1758-9193
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://alzres.biomedcentral.com/articles/10.1186/s13195-018-0352-4
info:eu-repo/semantics/altIdentifier/doi/10.1186/s13195-018-0352-4
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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
_version_ 1846781356554584064
score 12.982451

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