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

Autor: Tim Vanmierlo, Katie Lunnon, Dean Paes, Diego Mastroeni, Janou A. Y. Roubroeks, Daniel L.A. van den Hove, Ehsan Pishva, Elaine Delvaux, Paul D. Coleman, Roy Lardenoije, Melissa Schepers, Riccardo M. Carollo, Jos Prickaerts
Přispěvatelé: RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Aging
Pathology
Gene Expression
PROTEIN
Disease
PDE4D ISOFORMS
Cohort Studies
0302 clinical medicine
Medicine
Aged
80 and over
DNA methylation
General Neuroscience
Phosphodiesterase
Methylation
Alzheimer's disease
3. Good health
Isoenzymes
Real-time polymerase chain reaction
Cognitive impairment
Female
Gene isoform
medicine.medical_specialty
kinase
brain
camp-specific phosphodiesterase
Temporal lobe
03 medical and health sciences
Braak stage
Transcript variants
Alzheimer Disease
Humans
Cognitive Dysfunction
verbal word memory
Gene
Genetic Association Studies
Aged
IDENTIFICATION
business.industry
package
Cyclic Nucleotide Phosphodiesterases
Type 4
030104 developmental biology
Neurology (clinical)
Geriatrics and Gerontology
business
Phosphodiesterase 4D (PDE4D)
030217 neurology & neurosurgery
Developmental Biology
Zdroj: Neurobiology of Aging, 97, 56-64. Elsevier Science
ISSN: 0197-4580
Popis: 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. (C) 2020 The Authors. Published by Elsevier Inc. This work was financially supported by grants from ISAO/Alzheimer Nederland WE.03-2016-07, Young European Research Universities Network (YERUN), and the Baeter Laeve foundation. Additional funds have been provided by the Internationale Stichting Alzheimer Onderzoek (ISAO)/Alzheimer Netherlands (Award #11532; Funded by the Dorpmans-Wigmans Foundation) (DvdH), and by the Joint ProgrammeeNeurodegenerative Disease Research (JPND) for the EPI-AD consortium (http://www.neurodegenerationresearch.eu/wp-content/uploads/2015/10/Factsheet_EPI-AD.pdf).The project is supported through the following funding organizations under the aegis of JPND; The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw); United Kingdom, Medical Research Council; Germany, German Federal Ministry of Education and Research (BMBF); Luxembourg, National Research Fund (FNR). This project has received funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No. 643417. Prickaerts, J (corresponding author), Maastricht Univ, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands. jos.prickaerts@maastrichtuniversity.nl
Databáze: OpenAIRE
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