PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition

Neurobiol Aging. 2014 Sep;35(9):2072-8. doi: 10.1016/j.neurobiolaging.2014.03.023. Epub 2014 Mar 26.


The cyclic nucleotide cGMP is an important intracellular messenger for synaptic plasticity and memory function in rodents. Therefore, inhibition of cGMP degrading phosphodiesterases, like PDE9A, has gained interest as potential target for treatment of cognition deficits in indications like Alzheimer's disease (AD). In fact, PDE9A inhibition results in increased hippocampal long-term potentiation and exhibits procognitive effects in rodents. To date, however, no evidence has been published linking PDE9A inhibition to the pathologic hallmarks of AD such as amyloid beta (Aβ) deposition. Therefore, we investigated the role of PDE9A inhibition in an AD relevant context by testing its effects on Aβ-related deficits in synaptic plasticity and cognition. The PDE9A inhibitor BAY 73-6691 was found to restore long-term potentiation impaired by Aβ42 oligomers. Furthermore, we demonstrated that BAY 73-6691 enhanced cGMP levels in the hippocampus of APP transgenic tg2576 mice and improved memory performance of these mice. Altogether, our results support the hypothesis that inhibition of PDE9A could be a beneficial approach for the treatment of memory impairment in AD patients.

Keywords: Alzheimer's disease; Amyloid beta; BAY 73-6691; Cognition; Hippocampus; LTP; Object location task; PDE9; cGMP; tg2576.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / physiology
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / psychology
  • Amyloid beta-Peptides / adverse effects*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cognition / drug effects*
  • Cognition / physiology
  • Cyclic GMP / metabolism
  • Cyclic GMP / physiology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Long-Term Potentiation / genetics
  • Male
  • Memory / drug effects
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / genetics*
  • Peptide Fragments / adverse effects
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rats, Wistar


  • Amyloid beta-Peptides
  • BAY 73-6691
  • Peptide Fragments
  • Pyrazoles
  • Pyrimidines
  • amyloid beta-protein (1-42)
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • PDE9A protein, human
  • Cyclic GMP