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...

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Detalles Bibliográficos
Autores: 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
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
Descripción
Sumario: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.

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