The p53/NF-kappaB-dependent induction of sestrin2 by amyloid-beta peptides exerts antioxidative actions in neurons

Yi Heng Hsieh, A. Ching Chao, Yi Chun Lin, Shang Der Chen, Ding I. Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

6 Scopus citations


Accumulation of senile plaques mainly composed of neurotoxic amyloid-beta peptide (Aβ) is a pathological hallmark of Alzheimer's disease (AD). Sestrin2 inducible by various types of stressors is known to promote autophagy and exert antioxidative effects. In this work, we revealed the molecular mechanisms underlying Aβ induction of sestrin2 and tested whether antioxidation, in addition to autophagy regulation, also contributes to its neuroprotective effects in primary rat cortical neurons. We found that Aβ25-35 triggered nuclear translocation of p65 and p50, two subunits of nuclear factor-kappaB (NF-κB), and p53. Aβ25-35-induced sestrin2 expression was abolished by the p65 siRNA, the NF-κB inhibitor SN50, and the p53 inhibitor pifithrin-alpha (PFT-α). Further, Aβ25-35 enhanced binding of p50 and p53 to sestrin2 gene promoter that was abolished respectively by the p50 shRNA and PFT-α. Both p50 shRNA and PFT-α attenuated Aβ25-35-induced expression as well as nuclear translocation of all three transcription factors, namely p65, p50, and p53. Interestingly, p50 binding to the promoters of its target genes required p53 activity, whereas p50 also negatively regulated p53 binding to its target sequences. Suppression of sestrin2 expression by siRNA enhanced Aβ25-35- and Aβ1-42-induced production of reactive oxygen species (ROS), lipid peroxidation, and formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG). In contrast, overexpression of the sestrin2 N-terminal or C-terminal fragments neutralized Aβ25-35-induced ROS production. We concluded that Aβ-induced sestrin2 contributing to antioxidant effects in neurons is in part mediated by p53 and NF-κB, which also mutually affect the expression of each other.

Original languageEnglish
Pages (from-to)36-61
Number of pages26
JournalFree Radical Biology and Medicine
StatePublished - 06 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.


  • Alzheimer's disease
  • Autophagy
  • Cortical neurons
  • Oxidative stress
  • Sestrins


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