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

Dean Paes, Roy Lardenoije, Riccardo M. Carollo, Janou A.Y. Roubroeks, Melissa Schepers, Paul Coleman, Diego Mastroeni, Elaine Delvaux, Ehsan Pishva, Katie Lunnon, Tim Vanmierlo, Daniel van den Hove, Jos Prickaerts

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)56-64
Number of pages9
JournalNeurobiology of Aging
Volume97
DOIs
StatePublished - Jan 2021

Keywords

  • Alzheimer's disease
  • Braak stage
  • Cognitive impairment
  • DNA methylation
  • Phosphodiesterase 4D (PDE4D)
  • Transcript variants

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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