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

doi:10.3390/cells13121000

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	1000
Number of pages	21
Journal	Cells
Volume	13
Issue number	12
DOIs	https://doi.org/10.3390/cells13121000
Publication status	Published - 8 Jun 2024

Keywords

Alzheimer’s disease
cognition
cyclic nucleotide phosphodiesterases type 4B
microglia
synapse
Animals
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism
Mice
Mice, Transgenic
Alzheimer Disease/drug therapy pathology
Cognition/drug effects
Phosphodiesterase 4 Inhibitors/pharmacology therapeutic use administration & dosage
Microglia/drug effects metabolism pathology
Disease Models, Animal
Presenilin-1/genetics metabolism
Humans
Amyloid beta-Protein Precursor/genetics metabolism
Male

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Rombaut, B., Schepers, M., Tiane, A., Mussen, F., Koole, L., Kessels, S., Trippaers, C., Jacobs, R., Wouters, K., Willems, E., Veggel, L. V., Koulousakis, P., Deluyker, D., Bito, V., Prickaerts, J., Wens, I., Brône, B., van den Hove, D. L. A., & Vanmierlo, T. (2024). Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice. Cells, 13(12), Article 1000. https://doi.org/10.3390/cells13121000

@article{4665314b52814e07bb95c52290a1f06b,

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

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.",

keywords = "Alzheimer{\textquoteright}s disease, cognition, cyclic nucleotide phosphodiesterases type 4B, microglia, synapse, Animals, Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism, Mice, Mice, Transgenic, Alzheimer Disease/drug therapy pathology, Cognition/drug effects, Phosphodiesterase 4 Inhibitors/pharmacology therapeutic use administration & dosage, Microglia/drug effects metabolism pathology, Disease Models, Animal, Presenilin-1/genetics metabolism, Humans, Amyloid beta-Protein Precursor/genetics metabolism, Male",

author = "Ben Rombaut and Melissa Schepers and Assia Tiane and Femke Mussen and Lisa Koole and Sofie Kessels and Chlo{\"e} Trippaers and Ruben Jacobs and Kristiaan Wouters and Emily Willems and Veggel, {Lieve van} and Philippos Koulousakis and Dorien Deluyker and Virginie Bito and Jos Prickaerts and Inez Wens and Bert Br{\^o}ne and {van den Hove}, {Daniel L A} and Tim Vanmierlo",

year = "2024",

month = jun,

day = "8",

doi = "10.3390/cells13121000",

language = "English",

volume = "13",

journal = "Cells",

issn = "2073-4409",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "12",

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Rombaut, B, Schepers, M, Tiane, A , Mussen, F , Koole, L, Kessels, S, Trippaers, C, Jacobs, R, Wouters, K , Willems, E , Veggel, LV , Koulousakis, P, Deluyker, D, Bito, V, Prickaerts, J, Wens, I, Brône, B, van den Hove, DLA & Vanmierlo, T 2024, 'Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice', Cells, vol. 13, no. 12, 1000. https://doi.org/10.3390/cells13121000

TY - JOUR

T1 - Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice

AU - Rombaut, Ben

AU - Schepers, Melissa

AU - Tiane, Assia

AU - Mussen, Femke

AU - Koole, Lisa

AU - Kessels, Sofie

AU - Trippaers, Chloë

AU - Jacobs, Ruben

AU - Wouters, Kristiaan

AU - Willems, Emily

AU - Veggel, Lieve van

AU - Koulousakis, Philippos

AU - Deluyker, Dorien

AU - Bito, Virginie

AU - Prickaerts, Jos

AU - Wens, Inez

AU - Brône, Bert

AU - van den Hove, Daniel L A

AU - Vanmierlo, Tim

PY - 2024/6/8

Y1 - 2024/6/8

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - cognition

KW - cyclic nucleotide phosphodiesterases type 4B

KW - microglia

KW - synapse

KW - Animals

KW - Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism

KW - Mice

KW - Mice, Transgenic

KW - Alzheimer Disease/drug therapy pathology

KW - Cognition/drug effects

KW - Phosphodiesterase 4 Inhibitors/pharmacology therapeutic use administration & dosage

KW - Microglia/drug effects metabolism pathology

KW - Disease Models, Animal

KW - Presenilin-1/genetics metabolism

KW - Humans

KW - Amyloid beta-Protein Precursor/genetics metabolism

KW - Male

U2 - 10.3390/cells13121000

DO - 10.3390/cells13121000

M3 - Article

SN - 2073-4409

VL - 13

JO - Cells

JF - Cells

IS - 12

M1 - 1000

ER -

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

Abstract

Keywords

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