TY - JOUR
T1 - Increased isoform-specific phosphodiesterase 4D expression is associated with pathology and cognitive impairment in Alzheimer's disease
AU - Paes, Dean
AU - Lardenoije, Roy
AU - Carollo, Riccardo M.
AU - Roubroeks, Janou A.Y.
AU - Schepers, Melissa
AU - Coleman, Paul
AU - Mastroeni, Diego
AU - Delvaux, Elaine
AU - Pishva, Ehsan
AU - Lunnon, Katie
AU - Vanmierlo, Tim
AU - van den Hove, Daniel
AU - Prickaerts, Jos
N1 - Funding Information:
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 Programme–Neurodegenerative 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. We thank Dr. Ir. Jochen De Vry for primer and qPCR experiment design.
Funding Information:
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 Programme–Neurodegenerative 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 .
Publisher Copyright:
© 2020 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Braak stage
KW - Cognitive impairment
KW - DNA methylation
KW - Phosphodiesterase 4D (PDE4D)
KW - Transcript variants
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U2 - 10.1016/j.neurobiolaging.2020.10.004
DO - 10.1016/j.neurobiolaging.2020.10.004
M3 - Article
C2 - 33157432
AN - SCOPUS:85094976327
SN - 0197-4580
VL - 97
SP - 56
EP - 64
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -