Double-Edged Roles of Nitric Oxide Signaling on APP Processing and Amyloid-β Production In Vitro: Preliminary Evidence from Sodium Nitroprusside

Zheng Xu Cai, Hui Shu Guo, Che Wang, Min Wei, Cheng Cheng, Zhao Fei Yang, Yin Wang Chen, Wei Dong Le, Song Li

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is thought to be caused in part by the age-related accumulation of amyloid-β (Aβ) in the brain. Recent findings have revealed that nitric oxide (NO) modulates the processing of amyloid-β precursor protein (APP) and alters Aβ production; however, the previously presented data are contradictory and the underlying molecular mechanisms are still incomplete. Here, using human SH-SY5Y neuroblastoma cells stably transfected with wild-type APPwt695, we found that NO, derived from NO donor sodium nitroprusside (SNP), bi-directionally modulates APP processing in vitro. The data from ELISA and Western blot (WB) tests indicated that SNP at lower concentrations (0.01 and 0.1 μM) inhibits BACE1 expression, thus consequently suppresses APP β-cleavage and decreases Aβ production. In contrast, SNP at higher concentrations (10 and 20 μM) biases the APP processing toward the amyloidogenic pathway as evidenced by an increased BACE1 but a decreased ADAM10 expression, together with an elevated Aβ secretion. This bi-directional modulating activity of SNP on APP processing was completely blocked by specific NO scavenger c-PTIO, indicating NO-dependent mechanisms. Moreover, the anti-amyloidogenic activity of SNP is sGC/cGMP/PKG-dependent as evidenced by its reversal by sGC/PKG inhibitions, whereas the amyloidogenic activity of SNP is peroxynitrite-related and can be reversed by peroxynitrite scavenger uric acid. In summary, these present findings predict a double-edged role of NO in APP processing in vitro. Low (physiological) levels of NO inhibit the amyloidogenic processing of APP, whereas extra-high (pathological) concentrations of NO favor the amyloidogenic pathway of APP processing. This preliminary study may provide further evidence to clarify the molecular roles of NO and NO-related signaling in AD and supply potential molecular targets for AD treatment.

Original languageEnglish (US)
Pages (from-to)21-34
Number of pages14
JournalNeurotoxicity Research
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Amyloid-β
  • Amyloid-β precursor protein
  • Nitric oxide
  • Peroxynitrite
  • Sodium nitroprusside
  • sGC/cGMP/PKG signaling pathway

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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