Increased isoform-specific phosphodiesterase 4D expression is associated with pathology and cognitive impairment in Alzheimer's disease.

Aged Aged, 80 and over Alzheimer Disease / complications Brain / metabolism Cognitive Dysfunction / etiology Cohort Studies Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics Female Gene Expression / genetics Genetic Association Studies Humans Isoenzymes / genetics Male
Alzheimer’s disease Braak stage Cognitive impairment DNA methylation Phosphodiesterase 4D (PDE4D) Transcript variants

Journal

Neurobiology of aging
ISSN: 1558-1497
Titre abrégé: Neurobiol Aging
Pays: United States
ID NLM: 8100437

Informations de publication

Date de publication:
01 2021
Historique:
received: 09 04 2020
revised: 16 09 2020
accepted: 04 10 2020
pubmed: 7 11 2020
medline: 2 9 2021
entrez: 6 11 2020
Statut: ppublish

Résumé

Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and -D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD.

Identifiants

DOI: 10.1016/j.neurobiolaging.2020.10.004 PMID: 33157432
pubmed: 33157432
pii: S0197-4580(20)30313-4
doi: 10.1016/j.neurobiolaging.2020.10.004
pii:
doi:

Substances chimiques

Isoenzymes 0
Cyclic Nucleotide Phosphodiesterases, Type 4 EC 3.1.4.17

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

56-64

Subventions

Organisme : Medical Research Council
Pays : United Kingdom

Informations de copyright

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Auteurs

Dean Paes (D)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Department of Neuroimmunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.

Roy Lardenoije (R)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Department of Psychiatry and Psychotherapy, Universitätsmedizin Göttingen, Georg-August-Universität, Göttingen, Germany; Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.

Riccardo M Carollo (RM)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.

Janou A Y Roubroeks (JAY)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.

Melissa Schepers (M)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Department of Neuroimmunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.

Paul Coleman (P)

L.J. Roberts Center for Alzheimer's Research, Banner Sun Health Research Institute, Sun City, AZ, USA; Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.

Diego Mastroeni (D)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; L.J. Roberts Center for Alzheimer's Research, Banner Sun Health Research Institute, Sun City, AZ, USA; Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.

Elaine Delvaux (E)

L.J. Roberts Center for Alzheimer's Research, Banner Sun Health Research Institute, Sun City, AZ, USA; Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.

Ehsan Pishva (E)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.

Katie Lunnon (K)

Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.

Tim Vanmierlo (T)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Department of Neuroimmunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.

Daniel 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.

Jos Prickaerts (J)

Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address: jos.prickaerts@maastrichtuniversity.nl.

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Classifications MeSH

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