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Title: | Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-beta pathology | Authors: | PAES, Dean SCHEPERS, Melissa WILLEMS, Emily ROMBAUT, Ben TIANE, Assia Solomina, Yevgeniya Tibbo, Amy Blair, Connor Kyurkchieva, Elka Baillie, George S. Ricciarelli, Roberta Brullo, Chiara Fedele, Ernesto Bruno, Olga van den Hove, Daniel VANMIERLO, Tim Prickaerts, Jos |
Issue Date: | 2023 | Publisher: | SPRINGER BASEL AG | Source: | CELLULAR AND MOLECULAR LIFE SCIENCES, 80 (7) (Art N° 178) | 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-beta. 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-beta 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. | Notes: | Vanmierlo, T; Prickaerts, J (corresponding author), Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands.; Vanmierlo, T (corresponding author), Hasselt Univ, Biomed Res Inst, Dept Neurosci, Diepenbeek, Belgium. t.vanmierlo@maastrichtuniversity.nl; jos.prickaerts@maastrichtuniversity.nl |
Keywords: | Alzheimer's disease;CRISPR;Cas9;Phosphodiesterase 4D;APP;PS1 | Document URI: | http://hdl.handle.net/1942/40497 | ISSN: | 1420-682X | e-ISSN: | 1420-9071 | DOI: | 10.1007/s00018-023-04804-w | ISI #: | 001003638300001 | Rights: | The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-β pathology.pdf | Published version | 3.22 MB | Adobe PDF | View/Open |
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