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Acta Physiologica 2008; Volume 194, Supplement 665
The 59th National Congress of the Italian Physiological Society
9/17/2008-9/19/2008
Cagliari, Italy
SILDENAFIL IMPROVES SYNAPTIC FUNCTION, MEMORY AND AMYLOID-BETA LOAD IN AN ALZHEIMER MOUSE MODEL
Abstract number: P115
PUZZO1,3 D, STANISZEWSKI1 A, DENG2 SX, LIU1 S, ZHANG1 H, PRIVITERA1,3 L, SAPIENZA3 S, PALMERI3 A, LANDRY2 DW, ARANCIO1 O
1Dept. Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain,
2Dept. Medicine, Columbia University, New York, USA
3Dept. Physiological Sciences, University of Catania, Catania, Italy
Aim:
Memory loss, synaptic dysfunction and high levels of amyloid-b peptide (Ab) are major hallmarks of Alzheimer's disease (AD). Ab 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 Ab 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 Ab40 and Ab42 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 thetreatment of AD and other diseases associated with elevatedAb levels.
Supported by the NIH Grant NS049442 to O.A.
To cite this abstract, please use the following information:
Acta Physiologica 2008; Volume 194, Supplement 665 :P115