Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice
Ben Rombaut1,2, Melissa Schepers1,2,3, Assia Tiane1,2,3
1Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3500 Hasselt, Belgium.
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.
Insights
Long-term inhibition of phosphodiesterase 4B (PDE4B) using A33 improved memory and prevented synapse loss in Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Microglia activation contributes to synaptic loss in Alzheimer's disease (AD).
- Reduced cyclic adenosine monophosphate (cAMP) levels, linked to phosphodiesterase 4B (PDE4B), are implicated in AD pathology.
- Disease-associated microglia (DAM) phenotype is a hallmark of AD progression.
Purpose of the Study:
- To investigate the efficacy of long-term PDE4B inhibition with A33 in preventing synapse loss and cognitive decline in a mouse model of AD.
- To explore the cellular effects of PDE4B inhibition on microglial activity.
Main Methods:
- APPswe/PS1dE9 mice received daily A33 treatment from 20 days to 4 months of age.
- Cognitive function was assessed at 7-8 months of age.
- In vitro experiments examined the effect of PDE4B inhibition on microglial morphology.
Main Results:
- Prolonged A33 treatment significantly enhanced working and spatial memory in APPswe/PS1dE9 mice post-treatment.
- In vitro, PDE4B inhibition promoted microglial filopodia formation, suggesting a counteraction to microglial activation.
- A33 treatment demonstrated potential in mitigating AD-related cognitive deficits.
Conclusions:
- PDE4B is a potential therapeutic target for Alzheimer's disease.
- Early intervention with PDE4B inhibitors like A33 may offer a promising strategy to combat AD.
- Further in vivo research is warranted to confirm the prevention of the DAM phenotype.
