Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease
Abstract BACKGROUND AND PURPOSE: Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer...
| Autores: | , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2011 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/22826 |
| Acceso en línea: | https://hdl.handle.net/10171/22826 |
| Access Level: | acceso abierto |
| Palabra clave: | BDNF CDK5 GSK3β sildenafil p-tau Alzheimer's disease |
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Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's diseaseGarcia-Osta, A. (Ana)|||/items/6a828922-d55a-4aca-9dec-ccfb2a7380f8Aguirre, N. (Norberto)|||/items/14cf46d2-53c6-4060-a22b-8fb690ad81b3Franco, R. (Rafael)|||/items/11f971cd-f36c-4f89-b4d5-8269d33e93fcGarcia-Barroso, C. (C.)|||/items/56d7b5c1-8aab-4cbe-a92a-e7195b50044bPerez-Roldan, J.M. (J.M.)|||/items/0f6b57cd-a14d-4849-8b89-1fe81450bf7aPuerta, E. (Elena)|||/items/1dc4716b-b5b8-422b-bd27-2d153f66a3b8Ricobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924abHervias, I. (Isabel)|||/items/a2bc8f76-2803-4476-bcbc-cb40fc347ac4Cuadrado-Tejedor, M. (Mar)|||/items/8e19b277-1821-4ae8-9617-975de11dbdd1BDNFCDK5GSK3βsildenafilp-tauAlzheimer's diseaseAbstract BACKGROUND AND PURPOSE: Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated. EXPERIMENTAL APPROACH: Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil. KEY RESULTS: Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden. CONCLUSIONS AND IMPLICATIONS: Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease.Wiley-BlackwellDadun. Depósito Académico Digital Universidad de Navarra20122012-07-0420112011-12-0120112011-12-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/22826reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/228262026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease |
| title |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease |
| spellingShingle |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease Garcia-Osta, A. (Ana)|||/items/6a828922-d55a-4aca-9dec-ccfb2a7380f8 BDNF CDK5 GSK3β sildenafil p-tau Alzheimer's disease |
| title_short |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease |
| title_full |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease |
| title_fullStr |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease |
| title_full_unstemmed |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease |
| title_sort |
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease |
| dc.creator.none.fl_str_mv |
Garcia-Osta, A. (Ana)|||/items/6a828922-d55a-4aca-9dec-ccfb2a7380f8 Aguirre, N. (Norberto)|||/items/14cf46d2-53c6-4060-a22b-8fb690ad81b3 Franco, R. (Rafael)|||/items/11f971cd-f36c-4f89-b4d5-8269d33e93fc Garcia-Barroso, C. (C.)|||/items/56d7b5c1-8aab-4cbe-a92a-e7195b50044b Perez-Roldan, J.M. (J.M.)|||/items/0f6b57cd-a14d-4849-8b89-1fe81450bf7a Puerta, E. (Elena)|||/items/1dc4716b-b5b8-422b-bd27-2d153f66a3b8 Ricobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924ab Hervias, I. (Isabel)|||/items/a2bc8f76-2803-4476-bcbc-cb40fc347ac4 Cuadrado-Tejedor, M. (Mar)|||/items/8e19b277-1821-4ae8-9617-975de11dbdd1 |
| author |
Garcia-Osta, A. (Ana)|||/items/6a828922-d55a-4aca-9dec-ccfb2a7380f8 |
| author_facet |
Garcia-Osta, A. (Ana)|||/items/6a828922-d55a-4aca-9dec-ccfb2a7380f8 Aguirre, N. (Norberto)|||/items/14cf46d2-53c6-4060-a22b-8fb690ad81b3 Franco, R. (Rafael)|||/items/11f971cd-f36c-4f89-b4d5-8269d33e93fc Garcia-Barroso, C. (C.)|||/items/56d7b5c1-8aab-4cbe-a92a-e7195b50044b Perez-Roldan, J.M. (J.M.)|||/items/0f6b57cd-a14d-4849-8b89-1fe81450bf7a Puerta, E. (Elena)|||/items/1dc4716b-b5b8-422b-bd27-2d153f66a3b8 Ricobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924ab Hervias, I. (Isabel)|||/items/a2bc8f76-2803-4476-bcbc-cb40fc347ac4 Cuadrado-Tejedor, M. (Mar)|||/items/8e19b277-1821-4ae8-9617-975de11dbdd1 |
| author_role |
author |
| author2 |
Aguirre, N. (Norberto)|||/items/14cf46d2-53c6-4060-a22b-8fb690ad81b3 Franco, R. (Rafael)|||/items/11f971cd-f36c-4f89-b4d5-8269d33e93fc Garcia-Barroso, C. (C.)|||/items/56d7b5c1-8aab-4cbe-a92a-e7195b50044b Perez-Roldan, J.M. (J.M.)|||/items/0f6b57cd-a14d-4849-8b89-1fe81450bf7a Puerta, E. (Elena)|||/items/1dc4716b-b5b8-422b-bd27-2d153f66a3b8 Ricobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924ab Hervias, I. (Isabel)|||/items/a2bc8f76-2803-4476-bcbc-cb40fc347ac4 Cuadrado-Tejedor, M. (Mar)|||/items/8e19b277-1821-4ae8-9617-975de11dbdd1 |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
BDNF CDK5 GSK3β sildenafil p-tau Alzheimer's disease |
| topic |
BDNF CDK5 GSK3β sildenafil p-tau Alzheimer's disease |
| description |
Abstract BACKGROUND AND PURPOSE: Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated. EXPERIMENTAL APPROACH: Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil. KEY RESULTS: Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden. CONCLUSIONS AND IMPLICATIONS: Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease. |
| publishDate |
2011 |
| dc.date.none.fl_str_mv |
2011 2011-12-01 2011 2011-12-01 2012 2012-07-04 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/22826 |
| url |
https://hdl.handle.net/10171/22826 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Wiley-Blackwell |
| publisher.none.fl_str_mv |
Wiley-Blackwell |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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1869412686154956800 |
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15.300719 |