期刊
NEUROBIOLOGY OF AGING
卷 97, 期 -, 页码 56-64出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2020.10.004
关键词
Alzheimer's disease; Phosphodiesterase 4D (PDE4D); Transcript variants; DNA methylation; Braak stage; Cognitive impairment
资金
- ISAO/Alzheimer Nederland [WE.03-2016-07]
- Young European Research Universities Network (YERUN)
- Baeter Laeve foundation
- Internationale Stichting Alzheimer Onderzoek (ISAO)/Alzheimer Netherlands - Dorpmans-Wigmans Foundation [11532]
- Joint ProgrammeeNeurodegenerative Disease Research (JPND)
- Netherlands, 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)
- European Union [643417]
- JPND
Pharmacological inhibition of phosphodiesterase 4D (PDE4D) shows potential in restoring memory function in Alzheimer's disease (AD), but may lead to adverse effects. Increased expression of specific PDE4D isoforms in AD is associated with changes in DNA methylation and severity of pathology and cognitive impairment. Further studies should investigate the functional roles of specific PDE4D isoforms and the safety and efficacy of selective inhibition for memory restoration in AD.
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.
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