Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model.
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.
Puzzo
Daniela
D
Department 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.
Staniszewski
Agnieszka
A
Deng
Shi Xian
SX
Privitera
Lucia
L
Leznik
Elena
E
Liu
Shumin
S
Zhang
Hong
H
Feng
Yan
Y
Palmeri
Agostino
A
Landry
Donald W
DW
Arancio
Ottavio
O
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009483:Neuropsychological Tests; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011597:Psychomotor Performance; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013037:Spatial Behavior / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017362:Cyclic AMP Response Element-Binding Protein; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D006152:Cyclic GMP