Understanding PDE4's function in Alzheimer's disease; a target for novel therapeutic approaches

Abstract

Phosphodiesterases (PDEs) have long been considered as targets for the treatment of Alzheimer's disease (AD) and a substantial body of evidence suggests that one sub-family from the super-family of PDEs, namely PDE4D, has particular significance in this context. This review discusses the role of PDE4 in the orchestration of cAMP response element binding signaling in AD and outlines the benefits of targeting PDE4D specifically. We examine the limited available literature that suggests PDE4 expression does not change in AD brains together with reports that show PDE4 inhibition as an effective treatment in this age-related neurodegenerative disease. Actually, aging induces changes in PDE4 expression/activity in an isoform and brain-region specific manner that proposes a similar complexity in AD brains. Therefore, a more detailed account of AD-related alterations in cellular/tissue location and the activation status of PDE4 is required before novel therapies can be developed to target cAMP signaling in this disease.

Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau

“…PDE4D transcript has also been shown to be decreased in AD in the hippocampus, which may be related to neuronal loss (McLachlan et al, 2007). However, mRNA is not always indicative of protein levels, and there is still debate over the changes in PDE4D activity with age (Tibbo et al, 2019). Nonetheless, the current results demonstrated that PDE4D protein levels are significantly decreased in the aged FC, supporting human transcriptome studies.…”

“…cAMP-PKA Signaling in the FC vs. Hippocampus cAMP-PKA signaling is traditionally associated with enhanced plasticity and learning, e.g., in primitive organisms (Dudai et al, 1976;Tibbo et al, 2019), and in classic brain circuits such as the hippocampus (Kandel, 2012). However, cAMP signaling can impair the working memory functions of the newly evolved PFC.…”

“…PDE4s are of particular interest given their relatively high expression in brain and reported role in cognition (Richter et al, 2013). Specifically, the PDE4D subfamily has been proposed as a therapeutic target for AD given reported cognitive-enhancing effects of PDE4D inhibitors that are able to avoid negative gastrointestinal side-effects of other PDE4 inhibitors (Bruno et al, 2011;Tibbo et al, 2019). However, much of this research is based on studies of cognition linked to the hippocampus (Tibbo et al, 2019) and results may not be applicable across brain regions.…”

“…Specifically, the PDE4D subfamily has been proposed as a therapeutic target for AD given reported cognitive-enhancing effects of PDE4D inhibitors that are able to avoid negative gastrointestinal side-effects of other PDE4 inhibitors (Bruno et al, 2011;Tibbo et al, 2019). However, much of this research is based on studies of cognition linked to the hippocampus (Tibbo et al, 2019) and results may not be applicable across brain regions. Notably, elevated PDE4D expression uniquely distinguishes the PFC from other brain regions (Carlyle et al, 2017) and thus, likely plays an important role in PFC function.…”

Two Novel Pde11a Genetic Variants Increase Tau Phosphorylations in Early-onset Alzheimer's Disease

“…PDE11A4 also plays a role in systems consolidation, which has relevance for cognitive de cits [33]. Phosphodiesterases (PDEs) have been linked to mental processes of emotions, learning and memory, with implications in mood and cognitive disorders, including Huntington disease, Parkinson's disease and AD [34][35][36][37]. This evidence suggests that PDE11A plays a role in brain function and may also be involved in AD.…”