Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice

Neurobiol Aging. 2014 Mar;35(3):520-31. doi: 10.1016/j.neurobiolaging.2013.09.002. Epub 2013 Oct 7.

Abstract

Age-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aβ) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aβ production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aβ42 production and the increase of the Aβ42:Aβ40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging.

Keywords: APP processing; Aging; Apoptosis; BDNF; Bax/Bcl-2 ratio; Beta-amyloid; Caspase-3; Sildenafil.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Aging / pathology*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Brain / metabolism
  • Brain / pathology*
  • Brain-Derived Neurotrophic Factor / metabolism
  • CA1 Region, Hippocampal / metabolism
  • Caspase 3 / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / physiology*
  • Deoxyuracil Nucleotides / metabolism
  • Disease Models, Animal
  • Humans
  • Injections, Intraperitoneal
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Neuronal Plasticity / genetics
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • Phosphorylation
  • Piperazines / administration & dosage
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Purines / administration & dosage
  • Purines / pharmacology
  • Sildenafil Citrate
  • Sulfones / administration & dosage
  • Sulfones / pharmacology*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Amyloid beta-Peptides
  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Deoxyuracil Nucleotides
  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Purines
  • Sulfones
  • bcl-2-Associated X Protein
  • deoxyuridine triphosphate
  • Sildenafil Citrate
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Caspase 3