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.
Keywords: 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.
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