The AAPS Journal

, Volume 16, Issue 4, pp 649–657

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

  • Yushuang Deng
  • Xi Lu
  • Li Wang
  • Tao Li
  • Yubin Ding
  • Huimin Cao
  • Yuping Zhang
  • Xiuming Guo
  • Gang Yu
Research Article

DOI: 10.1208/s12248-014-9605-8

Cite this article as:
Deng, Y., Lu, X., Wang, L. et al. AAPS J (2014) 16: 649. doi:10.1208/s12248-014-9605-8

Abstract

Curcumin (CUR), a non-toxic polyphenol from Curcuma longa, has been investigated as a potential therapy with anti-inflammatory and anti-oxidative effects for Alzheimer’s disease (AD), which depicts features of chronic inflammatory environment resulting in cellular death. However, it remains largely unknown whether the anti-inflammatory effect of CUR in AD is associated with its property of CpG demethylation, which is another function of CUR with the most research interest during recent years. Neprilysin (NEP, EP24.11), a zinc-dependent metallopeptidase expressed relatively low in the brain, is emerging as a potent inhibitor of AKT/Protein Kinase B. In addition, hypermethylated promoter of NEP has been reported to be associated with decreases in NEP expression. In the present study, using bisulfite-sequencing PCR (BSP) assay, we showed that the CpG sites in NEP gene were hypermethylated both in wild-type mouse neuroblastoma N2a cells (N2a/wt) and N2a cells stably expressing human Swedish mutant amyloid precursor protein (APP) (N2a/APPswe) associated with familial early onset AD. CUR treatment induced restoration of NEP gene via CpG demethylation. This CUR-mediated upregulation of NEP expression was also concomitant with the inhibition of AKT, subsequent suppression of nuclear transcription factor-κB (NF-κB) and its downstream pro-inflammatory targets including COX-2, iNOS in N2a/APPswe cells. This study represents the first evidence on a link between CpG demethylation effect on NEP and anti-inflammation ability of CUR that may provide a novel mechanistic insight into the anti-inflammatory actions of CUR as well as new basis for using CUR as a therapeutic intervention for AD.

KEY WORDS

AKT/NF-κB signaling Alzheimer’s disease Curcumin DNA methylation Neprilysin 

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Yushuang Deng
    • 1
    • 2
  • Xi Lu
    • 1
    • 2
  • Li Wang
    • 3
  • Tao Li
    • 4
  • Yubin Ding
    • 5
  • Huimin Cao
    • 1
    • 2
  • Yuping Zhang
    • 1
  • Xiuming Guo
    • 1
  • Gang Yu
    • 1
  1. 1.Department of NeurologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingPeople’s Republic of China
  2. 2.Laboratory Research CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqingPeople’s Republic of China
  3. 3.Department of Bio-therapy and Hemato-oncologyChongqing Cancer InstituteChongqingPeople’s Republic of China
  4. 4.Department of OrthopaedicsThe Second Affiliated Hospital of Dalian Medical UniversityDalianPeople’s Republic of China
  5. 5.Department of Reproductive BiologyChongqing Medical UniversityChongqingPeople’s Republic of China

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