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Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D.

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Affiliations

  • 1. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.
      Authors
    • Sierksma AS 1
    • Pfau F 1
    • Philippens M 1
    • Steinbusch HW 1
    • Vanmierlo T 1
    • Prickaerts J 1
    (6 authors)
  • 2. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands; Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
      Authors
    • van den Hove DL 2
    (1 author)
  • 3. Department of Pharmacy, University of Genoa, Genoa, Italy.
      Authors
    • Bruno O 3
    (1 author)
  • 4. Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.
      Authors
    • Fedele E 4
    (1 author)
  • 5. Department of Experimental Medicine, Section of General Pathology, University of Genoa, Genoa, Italy.
      Authors
    • Ricciarelli R 5
    (1 author)

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Neuropharmacology, 22 Sep 2013, 77:120-130
https://doi.org/10.1016/j.neuropharm.2013.09.015 PMID: 24067928 

Abstract 

Phosphodiesterase type 4 inhibitors (PDE4-Is) have received increasing attention as cognition-enhancers and putative treatment strategies for Alzheimer's disease (AD). By preventing cAMP breakdown, PDE4-Is can enhance intracellular signal transduction and increase the phosphorylation of cAMP response element-binding protein (CREB) and transcription of proteins related to synaptic plasticity and associated memory formation. Unfortunately, clinical development of PDE4-Is has been seriously hampered by emetic side effects. The new isoform-specific PDE4D-I, GEBR-7b, has shown to have beneficial effects on memory at non-emetic doses. The aim of the current study was to investigate chronic cognition-enhancing effects of GEBR-7b in a mouse model of AD. To this extent, 5-month-old (5M) APPswe/PS1dE9 mice received daily subcutaneous injections with GEBR-7b (0.001 mg/kg) or vehicle for a period of 3 weeks, and were tested on affective and cognitive behavior at 7M. We demonstrated a cognition-enhancing potential in APPswe/PS1dE9 mice as their spatial memory function at 7M in the object location test was improved by prior GEBR-7b treatment. APPswe/PS1dE9 mice displayed lower levels of CREB phosphorylation, which remained unaltered after chronic GEBR-7b treatment, and higher levels of tau in the hippocampus. Hippocampal brain-derived neurotrophic factor levels and synaptic densities were not different between experimental groups and no effects were observed on hippocampal GSK3β and tau phosphorylation or Aβ levels. In conclusion, GEBR-7b can enhance spatial memory function in the APPswe/PS1dE9 mouse model of AD. Although the underlying mechanisms of its cognition-enhancing potential remain to be elucidated, PDE4D inhibition appears an interesting novel therapeutic option for cognitive deficits in AD.

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Internationale Stichting Alzheimer Onderzoek (ISAO) (2)