title: Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by progressive cognitive deficits and synaptic dysfunction. Over the last decade phosphodiesterase inhibitors (PDEIs) have received increasing attention as putative cognition enhancers and have been suggested as a novel treatment strategy for AD. Given their ability to prevent hydrolysis of cAMP and/or cGMP, they can stimulate the cAMP/protein kinase A (PKA)/cAMP element-binding protein (CREB) and cGMP/PKG/CREB pathway to enhance synaptic transmission by increasing CREB phosphorylation (pCREB) and brain-derived neurotrophic factor (BDNF) transcription. Based on previous research, we hypothesized that chronic PDE2I treatment would improve AD-related cognitive deficits, by decreasing amyloid-β (Aβ) plaque load, enhancing pCREB and BDNF levels and increasing synaptic density in the hippocampus of 8-month-old APPswe/PS1dE9 mice. Results indicated that chronic PDE2I treatment could indeed improve memory performance in APPswe/PS1dE9 mice, without affecting anxiety, depressive-like behavior or hypothalamus-pituitary-adrenal axis regulation. However, no treatment effects were observed on Aβ plaque load, pCREB or BDNF concentrations, or presynaptic density in the hippocampus, suggesting that other signaling pathways and/or effector molecules might be responsible for its cognition-enhancing effects. Presynaptic density in the stratum lucidum of the CA3 subregion was significantly higher in APPswe/PS1dE9 mice compared to WT controls, possibly reflecting a compensatory mechanism. In conclusion, PDEs in general, and PDE2 specifically, could be considered as promising therapeutic targets for cognition enhancement in AD, although the underlying mechanism of action remains to be elucidated. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Science, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
authors: Annerieke S R
authors: AS
authors: Sierksma
authors: Kris
authors: K
authors: Rutten
authors: Sebastian
authors: S
authors: Sydlik
authors: Somayeh
authors: S
authors: Rostamian
authors: Harry W M
authors: HW
authors: Steinbusch
authors: Daniel L A
authors: DL
authors: van den Hove
authors: Jos
authors: J
authors: Prickaerts
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control*; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018697:Nootropic Agents / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011897:Random Allocation; D021641:Recognition, Psychology / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects; D014227:Triazines / Q000627:therapeutic use
chemical_list: C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D007093:Imidazoles; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2