Long-term Ameliorative Effects of the Antidepressant Fluoxetine Exposure on Cognitive Deficits in 3 × TgAD Mice

Mol Neurobiol. 2017 Aug;54(6):4160-4171. doi: 10.1007/s12035-016-9952-9. Epub 2016 Jun 21.

Abstract

Fluoxetine, a selective serotonin reuptake inhibitor, is neuroprotective; therefore, it has been applied to treat some neurodegenerative disorders. For instance, chronic fluoxetine exposure has short-term effects on Alzheimer's disease (AD). However, the long-term ameliorative effects of fluoxetine exposure on AD have not been reported. In the present study, 6-month-old 3 × TgAD mice were treated with fluoxetine for 15 days, and then the influence of fluoxetine was detected at 20 days after the drug withdrawal. We found that chronic fluoxetine treatment ameliorated cognitive deficits of 3 × TgAD mice and increased the volume of the hippocampal CA1 and dentate gyrus (DG) with increased neuron number and dendritic spine density. Meanwhile, fluoxetine exposure also stimulated the long-term potentiation (LTP) in hippocampal DG. The synaptic-related protein expression increased via activation of the cyclic AMP response element binding (CREB) protein/brain-derived neurotrophic factor (BDNF) signaling pathway induced by fluoxetine exposure. Lastly, we found that fluoxetine treatment decreased beta-amyloid (Aβ) levels. These results further certified that fluoxetine may be a potent effective drug for AD.

Keywords: Alzheimer’s disease; BDNF; Cognitive; Fluoxetine; MRI.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / therapeutic use*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognition Disorders / drug therapy*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Fluoxetine / administration & dosage
  • Fluoxetine / therapeutic use*
  • Hippocampus / pathology
  • Mice, Transgenic
  • Neuronal Plasticity / drug effects
  • Neurons / drug effects
  • Neurons / pathology
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • tau Proteins
  • Fluoxetine