Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D.
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.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.
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Sierksma
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.
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van den Hove
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.
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Pfau
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.
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Philippens
Department of Pharmacy, University of Genoa, Genoa, Italy.
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Bruno
Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.
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Fedele
Department of Experimental Medicine, Section of General Pathology, University of Genoa, Genoa, Italy.
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Ricciarelli
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.
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Steinbusch
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.
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Vanmierlo
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands. Electronic address: jos.prickaerts@maastrichtuniversity.nl.
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Prickaerts
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007097:Imines / Q000494:pharmacology* / Q000627:therapeutic use; D018782:Maze Learning / Q000187:drug effects*; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C570687:GEBR-7b; D007097:Imines; D008565:Membrane Proteins; D009025:Morpholines; D058988:Phosphodiesterase 4 Inhibitors; D051528:Guanylate Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
AD; ANOVA; APP/PS1; Alzheimer's disease; Aβ; BDNF; CREB; Cognition; DMSO; EZM; FST; GEBR-7b; GSK3β; HPA axis; LTP; M; OF; OLT; PDE; PDE-Is; PKA; PSD95; Phosphodiesterase inhibitors; SEM; SIT; T; TrkB; WT; Y-maze; Y-maze spontaneous alternation test; amyloid-β; analysis of variance; brain-derived neurotrophic factor; cAMP; cAMP response element-binding protein; cyclic adenosine monophosphate; d2; dimethylsulphoxide; discrimination index of the OLT; e; elevated zero maze; exploration time during a trial of the OLT; forced swim test; glycogen synthase kinase 3β; hypothalamo-pituitary-adrenal axis; long-term potentiation; months of age; object location task; open field; p75 neurotrophin receptor; p75(NTR); pCREB; pGSK3β-Ser9; phosphodiesterase; phosphodiesterase inhibitors; phosphorylated CREB; phosphorylated GSK3β at serine 9; postsynaptic density 95; protein kinase A; s.c.; standard error of the mean; subcutaneous; sucrose intake test; trial of the OLT; tropomyosin-related kinase B; wild-type