Background: Alzheimer’s disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid-beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in double transgenic mice for amyloid precursor protein (APP:K670N,M671L) and presenilin-1 (PS1:M146V) (Trinchese et al, Ann Neurol. 2004, 55:801), termed APP/PS1 mice. In fact, long-term potentiation (LTP), a cellular model of synaptic plasticity that might underlie learning and memory, and spatial working memory, are impaired at early stages in APP/PS1 animals. Previous studies showed that, when modulating hippocampal synaptic plasticity, Abeta downregulates the NO/cGMP/CREB memory pathway and enhancement of the NO/cGMP signaling may restore Abeta-induced LTP impairment and CREB phosphorylation (Puzzo et al, J Neurosci. 2005,25:6887). Objective(s): To investigate whether a treatment with sildenafil, a compound that elevates cGMP levels by inhibiting phosphodiesterase 5, has a beneficial effect on synaptic and cognitive deficits in APP/PS1 mice. Methods: Basal synaptic transmission (BST) and LTP were recorded at the CA3-CA1 hippocampal connection. Contextual learning and spatial work- ing memory were studied through fear conditioning and radial-arm water- maze, respectively. CREB phosphorylation was analyzed on slices used for electrophysiology. Results: A brief 10 min application of sildenafil (1uM), synthesized as previously reported (Terrett et al, Bioorg Med Chem Lett. 1996, 6:1819), re-established normal potentiation and CREB phosphory- lation in 3 month-old APP/PS1 slices. A single injection of sildenafil (3mg/kg, i.p.) also improved contextual and spatial working memory in the double transgenic mice. Sildenafil was also capable of maintaining its protective effect over a prolonged period of time. Both APP/PS1 and WT mice were injected with sildenafil (3 mg/kg/day, ip) for 3 weeks, then the treatment was stopped for 9-12 weeks prior to testing. Mice were next subjected to the radial-arm water-maze task and re-tested for contextual learning. Results revealed a strong effect of treatment in APP/PS1 mice treated with sildenafil compared to APP/PS1 animals treated with vehicle. Electrophysiological studies showed an improvement of both BST and LTP in sildenafil-treated APP/PS1 mice; immunocytochemistry for phos- pho-CREB confirmed the beneficial effect of sildenafil in the transgenic mice. Conclusions: Sildenafil treatment ameliorates synaptic and cognitive dysfunction in AD mouse model.