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

Biochem Soc Trans. 2019 Oct 31;47(5):1557-1565. doi: 10.1042/BST20190763.

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.

Keywords: Alzheimer's disease; cAMP; cyclic nucleotide phosphodiesterases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology*
  • Animals
  • CREB-Binding Protein / metabolism
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Humans
  • Signal Transduction

Substances

  • Cyclic AMP
  • CREB-Binding Protein
  • Cyclic Nucleotide Phosphodiesterases, Type 4