AGEs induce cell death via oxidative and endoplasmic reticulum stresses in both human SH-SY5Y neuroblastoma cells and rat cortical neurons.
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.
Department of Senile Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China.
Qing-Qing
QQ
Yin
Chuan-Fang
CF
Dong
Si-Qin
SQ
Dong
Xue-Li
XL
Dong
Yan
Y
Hong
Xun-Yao
XY
Hou
Ding-Zhen
DZ
Luo
Jin-Jing
JJ
Pei
Xue-Ping
XP
Liu
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000633:toxicity*; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
D017127:Glycation End Products, Advanced