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J Neurosci. 2009 Jun 24;29(25):8075-86. doi: 10.1523/JNEUROSCI.0864-09.2009.

Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model.

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  • 1Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032, USA.

Abstract

Memory loss, synaptic dysfunction, and accumulation of amyloid beta-peptides (A beta) are major hallmarks of Alzheimer's disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after A beta elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of A beta levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated A beta levels.

PMID:
19553447
[PubMed - indexed for MEDLINE]
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