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.
Highlights
Phosphodiesterases (PDEs) are the only known enzyme super family that can degrade cyclic nucleotides and their role in cognition was realized in the 1970’s following study of a transgenic fly that was deficient in learning [1]
In human and animal models of autosomal dominant polycystic kidney disease (ADPKD), pharmacological activation of PDE4 puts a brake on cAMP signaling and profoundly inhibits cyst formation. Both cases outlined above illustrate the need for a deeper understanding of the molecular ‘fingerprint’ of cAMP signaling in Alzheimer’s disease (AD)
The effectiveness of inhibiting the PDE4D sub-family by pharmacological means or genetic silencing suggests that this enzyme has a unique coordinating role in cognition that is maladapted during AD
Summary
Phosphodiesterases (PDEs) are the only known enzyme super family that can degrade cyclic nucleotides and their role in cognition was realized in the 1970’s following study of a transgenic fly that was deficient in learning [1]. Disease-related errors in signal transduction stem from anomalous PDE function, which results in uncoordinated cAMP responses in certain regions of the brain that can affect memory formation and Aβ production [4]. Since the 1990s there have been many reports showing that the active-site targeting, PDE4–specific inhibitor rolipram can promote CREB signaling in several brain disease contexts [20,21,22,23,24].
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