Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice
Ben Rombaut,
Melissa Schepers,
Assia Tiane,
Femke Mussen,
Lisa Koole,
Sofie Kessels,
Chloë Trippaers,
Ruben Jacobs,
Kristiaan Wouters,
Emily Willems,
Lieve van Veggel,
Philippos Koulousakis,
Dorien Deluyker,
Virginie Bito,
Jos Prickaerts,
Inez Wens,
Bert Brône,
Daniel L. A. van den Hove,
Tim Vanmierlo
Affiliations
Ben Rombaut
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Melissa Schepers
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Assia Tiane
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Femke Mussen
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Lisa Koole
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Sofie Kessels
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Chloë Trippaers
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Ruben Jacobs
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Kristiaan Wouters
Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), 6229 ER Maastricht, The Netherlands
Emily Willems
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Lieve van Veggel
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Philippos Koulousakis
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Dorien Deluyker
UHasselt, Cardio & Organ Systems (COST), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium
Virginie Bito
UHasselt, Cardio & Organ Systems (COST), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium
Jos Prickaerts
Department Psychiatry and Neuropsychology, Mental Health and Neuroscience Institute (MHeNs), Division Translational Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
Inez Wens
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Bert Brône
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Daniel L. A. van den Hove
Department Psychiatry and Neuropsychology, Mental Health and Neuroscience Institute (MHeNs), Division Translational Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
Tim Vanmierlo
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium
Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer’s disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7–8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their ‘disease-associated microglia (DAM)’ phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.
