title: Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Division of Neurosciences, CIMA, University of Navarra, Avenida Pio XII 55, Pamplona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cuadrado-Tejedor
authors.forename: I
authors.initials: I
authors.lastname: Hervias
authors.forename: A
authors.initials: A
authors.lastname: Ricobaraza
authors.forename: E
authors.initials: E
authors.lastname: Puerta
authors.forename: J M
authors.initials: JM
authors.lastname: Pérez-Roldán
authors.forename: C
authors.initials: C
authors.lastname: García-Barroso
authors.forename: R
authors.initials: R
authors.lastname: Franco
authors.forename: N
authors.initials: N
authors.lastname: Aguirre
authors.forename: A
authors.initials: A
authors.lastname: García-Osta
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005239:Fear; D007150:Immunohistochemistry; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C092069:activity regulated cytoskeletal-associated protein; D016875:tau Proteins; D000068677:Sildenafil Citrate