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

NEUROBIOLOGY OF AGING

卷:97

Article

Paes, Dean^1,2  Lardenoije, Roy^1,3,4  Carollo, Riccardo M.¹  Roubroeks, Janou A. Y.^1,5  Schepers, Melissa^1,2  Coleman, Paul^6,7  Mastroeni, Diego^1,6,7  Delvaux, Elaine^6,7  Pishva, Ehsan^1,5  Lunnon, Katie⁵  Vanmierlo, Tim^1,2  van den Hove, Daniel^1,8  Prickaerts, Jos¹ 

[1] Maastricht Univ, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands

[2] Hasselt Univ, Dept Neuroimmunol, Biomed Res Inst, Diepenbeek, Belgium

[3] Georg August Univ, Dept Psychiat & Psychotherapy, Univ Med Gottingen, Gottingen, Germany

[4] Harvard Med Sch, Dept Psychiat, McLean Hosp, Belmont, MA USA

[5] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England

[6] Banner Sun Hlth Res Inst, LJ Roberts Ctr Alzheimers Res, Sun City, AZ USA

[7] Arizona State Univ, Biodesign Inst, Neurodegenerat Dis Res Ctr, Tempe, AZ USA

[8] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany

关键词: Alzheimer's disease;    Phosphodiesterase 4D (PDE4D);    Transcript variants;    DNA methylation;    Braak stage;    Cognitive impairment;   

DOI  :  10.1016/j.neurobiolaging.2020.10.004

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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