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Cell Biology and Toxicology

, Volume 35, Issue 6, pp 573–588 | Cite as

Peroxiredoxin 4 ameliorates amyloid beta oligomer-mediated apoptosis by inhibiting ER-stress in HT-22 hippocampal neuron cells

  • Min Kyoung Kam
  • Dong Gil Lee
  • Bokyung Kim
  • Hyun-Shik Lee
  • Sang-Rae Lee
  • Yong Chul Bae
  • Dong-Seok LeeEmail author
Original Article

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder caused by amyloid beta oligomers (AβO), which induce cell death by triggering oxidative stress and endoplasmic reticulum (ER) stress. Oxidative stress is regulated by antioxidant enzymes, including peroxiredoxins. Peroxiredoxins (Prx) are classified into six subtypes, based on their localization and cysteine residues, and protect cells by scavenging hydrogen peroxide (H2O2). Peroxiredoxin 4 (Prx4) is unique in being localized to the ER; however, whether Prx4 protects neuronal cells from AβO-induced toxicity remains unclear, although Prx4 expression is upregulated in AβO-induced oxidative stress and ER stress. In this study, we established HT-22 cells in which Prx4 was either overexpressed or silenced to investigate its role in AβO-induced toxicity. AβO-stimulation of HT-22 cells with overexpressed Prx4 caused decreases in both AβO-induced ROS and ER stress (followed by ER expansion). In contrast, AβO stimulation caused increases in both ROS and ER stress that were notably higher in HT-22 cells with silenced Prx4 expression than in HT-22 cells. Consequently, Prx4 overexpression decreased apoptotic cell death and ameliorated the AβO-induced increase in intracellular Ca2+. Therefore, we conclude that Prx4 has a protective effect against AβO-mediated oxidative stress, ER stress, and neuronal cell death. Furthermore, these results suggest that Prx4 may be a target for preventing AβO toxicity in AD.

Graphical abstract

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Keywords

Alzheimer’s disease Amyloid beta oligomer Peroxiredoxin 4 Oxidative stress Endoplasmic reticulum stress 

Abbreviations

AβO

Amyloid beta oligomer

ER

Endoplasmic reticulum

NAC

N-acetylcysteine

Prx4

Peroxiredoxin 4

TUDCA

Tauroursodeoxycholic acid

Notes

Author’s contribution

M. K. Kam conceived the study; performed the cell culture of HT-22 cells, western blotting analysis, and confocal imaging; and collected and interpreted the data. D. G. Lee and B. Kim performed data collection, analysis, and interpretation. H-S. Lee, S-R. Lee, and Y. C. Bae designed the study and arranged for financial support. D. S. Lee conceived of and designed the study; analyzed and interpreted data; wrote the manuscript; arranged for financial support; and arranged for final approval of the manuscript after receiving input from all authors.

Funding

This research was supported by grants from the KRIBB Research Initiative Program (KGM4621922) and the National Research Foundation of Korea funded by the Republic of Korea government (NRF-2015R1A4A1042271, 2017R1A2B4008176, and 2017R1A5A2015391).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

10565_2019_9477_MOESM1_ESM.pdf (253 kb)
ESM 1 (PDF 252 kb)

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.School of Life Sciences, BK21 Plus KNU Creative BioResearch GroupKyungpook National UniversityDaeguRepublic of Korea
  2. 2.Institute for Pediatric Regenerative MedicineShriners Hospitals for Children/UC Davis School of MedicineSacramentoUSA
  3. 3.Department of NeurologySchool of Medicine, UC DavisDavisUSA
  4. 4.National Primate Research CenterKorea Research Institute of Bioscience and Biotechnology (KRIBB)Chungcheonbuk-doRepublic of Korea
  5. 5.Department of Anatomy and Neurobiology, School of DentistryKyungpook National UniversityDaeguRepublic of Korea

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