Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease
Open Access
- 31 May 2011
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 164 (8), 2029-2041
- https://doi.org/10.1111/j.1476-5381.2011.01517.x
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.Keywords
This publication has 79 references indexed in Scilit:
- Effect size of reference memory deficits in the Morris water maze in Tg2576 miceBehavioural Brain Research, 2010
- Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients With Mild Alzheimer DiseaseA Randomized Controlled TrialJAMA, 2009
- Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's diseaseNature Medicine, 2009
- Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaquesPsychopharmacology, 2007
- Role of Cyclin-Dependent Kinase 5 in the Neurodegenerative Process Triggered by Amyloid-Beta and Prion Peptides: Implications for Alzheimer’s Disease and Prion-Related EncephalopathiesCellular and Molecular Neurobiology, 2007
- Presenilin‐1 is an unprimed glycogen synthase kinase‐3β substrateFEBS Letters, 2006
- Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3βFEBS Letters, 2002
- Glycogen synthase kinase 3β is identical to tau protein kinase I generating several epitopes of paired helical filamentsFEBS Letters, 1993
- Glycogen synthase kinase‐3 and the Alzheimer‐like state of microtubule‐associated protein tauFEBS Letters, 1992
- Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: Generation of paired helical filament epitopes and neuronal localisation of the kinaseNeuroscience Letters, 1992