Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-β pathology

Paes, D. et al. (2023) Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-β pathology. Cellular and Molecular Life Sciences, 80(7), 178. (doi: 10.1007/s00018-023-04804-w) (PMID:37306762) (PMCID:PMC10261250)

Abstract

Inhibition of phosphodiesterase 4D (PDE4D) enzymes has been investigated as therapeutic strategy to treat memory problems in Alzheimer’s disease (AD). Although PDE4D inhibitors are effective in enhancing memory processes in rodents and humans, severe side effects may hamper their clinical use. PDE4D enzymes comprise different isoforms, which, when targeted specifically, can increase treatment efficacy and safety. The function of PDE4D isoforms in AD and in molecular memory processes per se has remained unresolved. Here, we report the upregulation of specific PDE4D isoforms in transgenic AD mice and hippocampal neurons exposed to amyloid-β. Furthermore, by means of pharmacological inhibition and CRISPR-Cas9 knockdown, we show that the long-form PDE4D3, -D5, -D7, and -D9 isoforms regulate neuronal plasticity and convey resilience against amyloid-β in vitro. These results indicate that isoform-specific, next to non-selective, PDE4D inhibition is efficient in promoting neuroplasticity in an AD context. Therapeutic effects of non-selective PDE4D inhibitors are likely achieved through actions on long isoforms. Future research should identify which long PDE4D isoforms should be specifically targeted in vivo to both improve treatment efficacy and reduce side effects.

• Item Type: Articles
• Additional Information: This work was supported by Alzheimer Nederland [Grant WE.03–2016-07].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tibbo, Dr Amy and Baillie, Professor George and Blair, Dr Connor and Kyurkchieva, Ms Elka
• Authors: Paes, D., Schepers, M., Willems, E., Rombaut, B., Tiane, A., Solomina, Y., Tibbo, A., Blair, C., Kyurkchieva, E., Baillie, G. S., Ricciarelli, R., Brullo, C., Fedele, E., Bruno, O., van den Hove, D., Vanmierlo, T., and Prickaerts, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Cellular and Molecular Life Sciences
• Publisher: Springer
• ISSN: 1420-682X
• ISSN (Online): 1420-9071
• Published Online: 12 June 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Cellular and Molecular Life Sciences 80(7): 178
• Publisher Policy: Reproduced under a Creative Commons License