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Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D.
Neuropharmacology. 2014 Feb; 77:120-30.N

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.

Authors+Show Affiliations

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.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.Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.Department of Pharmacy, University of Genoa, Genoa, Italy.Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.Department of Experimental Medicine, Section of General Pathology, University of Genoa, Genoa, Italy.Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24067928

Citation

Sierksma, A S R., et al. "Improvement of Spatial Memory Function in APPswe/PS1dE9 Mice After Chronic Inhibition of Phosphodiesterase Type 4D." Neuropharmacology, vol. 77, 2014, pp. 120-30.
Sierksma AS, van den Hove DL, Pfau F, et al. Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology. 2014;77:120-30.
Sierksma, A. S., van den Hove, D. L., Pfau, F., Philippens, M., Bruno, O., Fedele, E., Ricciarelli, R., Steinbusch, H. W., Vanmierlo, T., & Prickaerts, J. (2014). Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology, 77, 120-30. https://doi.org/10.1016/j.neuropharm.2013.09.015
Sierksma AS, et al. Improvement of Spatial Memory Function in APPswe/PS1dE9 Mice After Chronic Inhibition of Phosphodiesterase Type 4D. Neuropharmacology. 2014;77:120-30. PubMed PMID: 24067928.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. AU - Sierksma,A S R, AU - van den Hove,D L A, AU - Pfau,F, AU - Philippens,M, AU - Bruno,O, AU - Fedele,E, AU - Ricciarelli,R, AU - Steinbusch,H W M, AU - Vanmierlo,T, AU - Prickaerts,J, Y1 - 2013/09/22/ PY - 2013/05/22/received PY - 2013/08/21/revised PY - 2013/09/09/accepted PY - 2013/9/27/entrez PY - 2013/9/27/pubmed PY - 2014/8/27/medline KW - AD KW - ANOVA KW - APP/PS1 KW - Alzheimer's disease KW - Aβ KW - BDNF KW - CREB KW - Cognition KW - DMSO KW - EZM KW - FST KW - GEBR-7b KW - GSK3β KW - HPA axis KW - LTP KW - M KW - OF KW - OLT KW - PDE KW - PDE-Is KW - PKA KW - PSD95 KW - Phosphodiesterase inhibitors KW - SEM KW - SIT KW - T KW - TrkB KW - WT KW - Y-maze KW - Y-maze spontaneous alternation test KW - amyloid-β KW - analysis of variance KW - brain-derived neurotrophic factor KW - cAMP KW - cAMP response element-binding protein KW - cyclic adenosine monophosphate KW - d2 KW - dimethylsulphoxide KW - discrimination index of the OLT KW - e KW - elevated zero maze KW - exploration time during a trial of the OLT KW - forced swim test KW - glycogen synthase kinase 3β KW - hypothalamo-pituitary-adrenal axis KW - long-term potentiation KW - months of age KW - object location task KW - open field KW - p75 neurotrophin receptor KW - p75(NTR) KW - pCREB KW - pGSK3β-Ser9 KW - phosphodiesterase KW - phosphodiesterase inhibitors KW - phosphorylated CREB KW - phosphorylated GSK3β at serine 9 KW - postsynaptic density 95 KW - protein kinase A KW - s.c. KW - standard error of the mean KW - subcutaneous KW - sucrose intake test KW - trial of the OLT KW - tropomyosin-related kinase B KW - wild-type SP - 120 EP - 30 JF - Neuropharmacology JO - Neuropharmacology VL - 77 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/24067928/Improvement_of_spatial_memory_function_in_APPswe/PS1dE9_mice_after_chronic_inhibition_of_phosphodiesterase_type_4D_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(13)00422-X DB - PRIME DP - Unbound Medicine ER -