Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice

Author:

Rombaut Ben12ORCID,Schepers Melissa123,Tiane Assia123,Mussen Femke124,Koole Lisa12ORCID,Kessels Sofie1ORCID,Trippaers Chloë15ORCID,Jacobs Ruben1,Wouters Kristiaan67ORCID,Willems Emily12,Veggel Lieve van123ORCID,Koulousakis Philippos12,Deluyker Dorien8,Bito Virginie8ORCID,Prickaerts Jos2ORCID,Wens Inez123,Brône Bert1ORCID,van den Hove Daniel L. A.29ORCID,Vanmierlo Tim123ORCID

Affiliation:

1. Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium

2. Department Psychiatry and Neuropsychology, Mental Health and Neuroscience Institute (MHeNs), Division Translational Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands

3. University MS Center (UMSC) Hasselt, 3900 Pelt, Belgium

4. Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium

5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA

6. Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), 6229 ER Maastricht, The Netherlands

7. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands

8. UHasselt, Cardio & Organ Systems (COST), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium

9. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, 97070 Wuerzburg, Germany

Abstract

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.

Funder

Fonds Wetenschappelijk Onderzoek

BAEF

Publisher

MDPI AG

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