Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Oct 31;47(5):1557-1565.
doi: 10.1042/BST20190763.

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

Amy J Tibbo  1 , Gonzalo S Tejeda  1 , George S Baillie  1
Affiliations
Review

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

Amy J Tibbo et al. Biochem Soc Trans. .

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.

PubMed Disclaimer

Conflict of interest statement

The Authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Schematic representation of the four genes of the PDE4 family.
Each gene generates multiple isoform variants with unique N-terminal (Nt) regions encoded by distinct specific exons (in red). PDE4 isoforms are classified upon their regulatory regions UCR1 (dots pattern) and UCR2 (line pattern). All isoforms within a specific PDE4 sub-family have identical C-terminal (Ct) regions, except the inactive PDE4A7 that contains a unique 14-residue Ct end.
Figure 2.
Figure 2.. Hypothetical neuronal model of cAMP depletion in AD leading to memory deficits.
Aberrant levels of cAMP can be a consequence of an inactivation of AC by Aβ peptide and BACE1 action or a higher activity of PDE4 in neurons. The subsequent decline in PKA action leads to a decrease in proteasomal activity associated with tau accumulation, a down-regulation of CREB signaling and a reduction in Aβ physiological functions.
See this image and copyright information in PMC

References

    1. Dudai Y., Jan Y.N., Byers D., Quinn W.G. and Benzer S. (1976) Dunce, a mutant of Drosophila deficient in learning. Proc. Natl Acad. Sci. U.S.A. 73, 1684–1688 10.1073/pnas.73.5.1684 - DOI - PMC - PubMed
    1. Byers D., Davis R.L. and Kiger J.A. Jr (1981) Defect in cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophila melanogaster. Nature 289, 79–81 10.1038/289079a0 - DOI - PubMed
    1. Bolger G., Michaeli T., Martins T., St John T., Steiner B., Rodgers L. et al. (1993) A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol. Cell Biol 13, 6558–6571 10.1128/MCB.13.10.6558 - DOI - PMC - PubMed
    1. Ricciarelli R. and Fedele E. (2018) cAMP, cGMP and amyloid β: three ideal partners for memory formation. Trends Neurosci. 41, 255–266 10.1016/j.tins.2018.02.001 - DOI - PubMed
    1. Francis S.H., Houslay M.D. and Conti M. (2011) Phosphodiesterase inhibitors: factors that influence potency, selectivity, and action. Handb. Exp. Pharmacol. 204, 47–84 10.1007/978-3-642-17969-3_2 - DOI - PubMed

Publication types

MeSH terms

Substances