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

Autor: Paes D; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.; Department of Neuroscience, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium., Schepers M; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.; Department of Neuroscience, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium., Willems E; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.; Department of Neuroscience, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium., Rombaut B; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.; Department of Neuroscience, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium., Tiane A; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.; Department of Neuroscience, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium., Solomina Y; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands., Tibbo A; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Blair C; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Kyurkchieva E; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Baillie GS; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Ricciarelli R; Section of General Pathology, Department of Experimental Medicine, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy.; IRCCS Ospedale Policlinico San Martino, Genoa, Italy., Brullo C; Section of Medicinal Chemistry, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy., Fedele E; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Section of Pharmacology and Toxicology, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy., Bruno O; Section of Medicinal Chemistry, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy., van den Hove D; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.; Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany., Vanmierlo T; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. t.vanmierlo@maastrichtuniversity.nl.; Department of Neuroscience, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium. t.vanmierlo@maastrichtuniversity.nl., Prickaerts J; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. jos.prickaerts@maastrichtuniversity.nl.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2023 Jun 12; Vol. 80 (7), pp. 178. Date of Electronic Publication: 2023 Jun 12.
DOI: 10.1007/s00018-023-04804-w
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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