Phosphodiesterase 4B: Master Regulator of Brain Signaling

Abstract

Phosphodiesterases (PDEs) are the only superfamily of enzymes that have the ability to break down cyclic nucleotides and, as such, they have a pivotal role in neurological disease and brain development. PDEs have a modular structure that allows targeting of individual isoforms to discrete brain locations and it is often the location of a PDE that shapes its cellular function. Many of the eleven different families of PDEs have been associated with specific diseases. However, we evaluate the evidence, which suggests the activity from a sub-family of the PDE4 family, namely PDE4B, underpins a range of important functions in the brain that positions the PDE4B enzymes as a therapeutic target for a diverse collection of indications, such as, schizophrenia, neuroinflammation, and cognitive function.

Sex-stratified single-cell RNA-Seq analysis identifies sex-specific and cell type-specific transcriptional responses in Alzheimer’s disease across two brain regions.

“…We observed upregulation of axon sprouting in response to injury in males, as well as an enriched upregulated pathway in axonogenesis regulation in females (Supplementary Table 6). Interestingly, a cluster of the PDE4B-DISC1-complex, with important functions in cAMP-regulated signal transduction and synaptic plasticity, 59 was downregulated in females.…”

“…The phosphodiesterase 4B (PDE4B) enzyme was previously shown to be pro-inflammatory in microglia and is currently under study as a therapeutic target for neuroinflammation and cognitive function impairment 59 .…”

Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue

“…The PDE4B gene is abundantly expressed throughout the brain and in several inflammatory cells, including neutrophils, monocytes/macrophages, and microglia, as well as being involved in inflammatory reactions. In addition, increasing cAMP levels are known to exert antiinflammatory effects [96]. To our knowledge, no research results are available yet on specific PDE4B gene inhibition in an ischemic stroke setting.…”

“…Furthermore, brain RNA sequencing results show that both the PDE4A and C genes are the least expressed PDE4 genes throughout the brain [97]. Even though PDE4A and PDE4C are also expressed in inflammatory cells including macrophages and microglia [96], their low brain expression patterns render them less interesting targets in neurodegenerative disorders. Interestingly, variations in the PDE4D gene have been associated with an increased risk of ischemic stroke even though conflicting results have been published on this manner.…”

Special Issue on “New Advances in Cyclic AMP Signalling”—An Editorial Overview

“…Moreover, they describe how different PDE isoforms (including PDE1C and PDE4C) control cyclic AMP oscillations in a nanodomain-specific manner in the sensory primary cilium compartment [ 48 ]. Finally, in the review conducted by Tibbo and Baillie, the authors describe the functional role of PDE4B in brain [ 49 ]. In particular, they describe a key role for a multi-protein complex encompassing Nuclear Distribution Factor-E-like (NDEL1) and its orthologue NDE1, Lissencephaly (LIS1), Disrupted-in-Schizophrenia 1 (DISC1), and PDE4B in the control of neuronal signalling linked to psychiatric disorders, probably through the regulation of the local activity of PKA [ 49 ].…”