Sildenafil improves synaptic function, memory and Amyloid-beta load in an Alzheimer Mouse Model

Aim: Memory loss, synaptic dysfunction and high levels of amyloid-β peptide (Aβ) are major hallmarks of Alzheimer’s disease (AD). Aβ down-regulates the nitric oxide/cGMP/c-AMP Responsive Element Binding Protein (CREB) cascade. The aim of this study was to investigate whether increasing cGMP levels through phosphodiesterase 5 (PDE5) inhibitors has a beneficial effect against AD phenotype. Methods: Double transgenic mice expressing both the human APP (K670M:N671L) and PS1 (M146L) (line 6.2) mutations were compared to WT littermates. We performed electrophysiological recordings to assess synaptic function (basal synaptic transmission and long-term potentiation), behavioural memory tests (radial arm water maze, Morris water maze and fear conditioning), immunocytochemistry for p-CREB and Aβ levels measurements. We assessed both the short- and long-term effects of sildenafil. Results: The PDE5 inhibitor sildenafil was beneficial against the AD phenotype in APP/PS1 mice. Sildenafil rescued synaptic and memory deficits. It re-established the increase in phosphorylation of the transcription factor and memory molecule CREB and caused a reduction in Aβ40 and Aβ42 levels. Most importantly, the inhibitor exerted its effect not only immediately, but also for a prolonged period beyond the drug administration. Conclusion: PDE5 inhibitors have potential for the treatment of AD and other diseases associated with elevated Aβ levels. Supported by the NIH Grant NS049442 to O.A.