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AGEs Induce Cell Death via Oxidative and Endoplasmic Reticulum Stresses in Both Human SH-SY5Y Neuroblastoma Cells and Rat Cortical Neurons

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Abstract

Advanced glycation endproducts (AGEs) are elevated in aging and neurodegenerative diseases such as Alzheimer’s disease (AD), and they can stimulate the generation of reactive oxygen species (ROSs) via NADPH oxidase, induce oxidative stress that lead to cell death. In the current study, we investigated the molecular events underlying the process that AGEs induce cell death in SH-SY5Y cells and rat cortical neurons. We found: (1) AGEs increase intracellular ROSs; (2) AGEs cause cell death after ROSs increase; (3) oxidative stress-induced cell death is inhibited via the blockage of AGEs receptor (RAGE), the down-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and the increase of scavenging by anti-oxidant alpha-lipoic acid (ALA); (4) endoplasmic reticulum (ER) stress was triggered by AGE-induced oxidative stress, resulting in the activation of C/EBP homologous protein (CHOP) and caspase-12 that consequently initiates cell death, taurine-conjugated ursodeoxycholic acid (TUDCA) inhibited AGE-induced ER stress and cell death. Blocking RAGE–NADPH oxidase, and RAGE–NADPH oxidase–ROSs and ER stress scavenging pathways could efficiently prevent the oxidative and ER stresses, and consequently inhibited cell death. Our results suggest a new prevention and or therapeutic approach in AGE-induced cell death.

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Abbreviations

AGEs:

Advanced glycation endproducts

ROSs:

Reactive oxygen species

RAGE:

AGEs receptor

NADPH:

Nicotinamide adenine dinucleotide phosphate

ALA:

Alpha-lipoic acid

ER:

Endoplasmic reticulum

MDA:

Malondialdehyde

SOD:

Superoxide dismutase

GSH-Px:

Glutathione peroxidase

GR:

Glutathione reductase

CAT:

Catalase

AIF:

Apoptosis inducing factor

UPR:

Unfolded protein response

GRP78:

Glucose-regulated protein 78

eIF2α:

Eukaryotic translation initiation factor 2

RAGE-ab:

RAGE-neutralizing antibody

DPI:

Diphenylene iodonium

BSA:

Bovine serum aluminum

CHOP:

C/EBP homologous protein

DCFH-DA:

2′,7′-Dichlorofluorescein diacetate

LDH:

Lactate dehydrogenase

PERK:

Double-stranded RNA-activated protein kinase-like ER kinase

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 30971036) and Shandong Provincial Natural Science Foundation of China (No. Y2008C13).

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Authors and Affiliations

  1. Department of Senile Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China

    Qing-Qing Yin, Chuan-Fang Dong, Si-Qin Dong, Yan Hong, Xun-Yao Hou, Ding-Zhen Luo & Xue-Ping Liu

  2. Department of Anti-Ageing, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China

    Xue-Li Dong & Xue-Ping Liu

  3. Department of KI-Alzheimer Disease Research Center, Karolinska Institutet, 14186, Stockholm, Sweden

    Jin-Jing Pei

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  1. Qing-Qing Yin
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Correspondence to Jin-Jing Pei or Xue-Ping Liu.

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Yin, QQ., Dong, CF., Dong, SQ. et al. AGEs Induce Cell Death via Oxidative and Endoplasmic Reticulum Stresses in Both Human SH-SY5Y Neuroblastoma Cells and Rat Cortical Neurons. Cell Mol Neurobiol 32, 1299–1309 (2012). https://doi.org/10.1007/s10571-012-9856-9

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