Uptake of silica nanoparticles: neurotoxicity and Alzheimer-like pathology in human SK-N-SH and mouse neuro2a neuroblastoma cells.
Growing concern has been raised over the potential adverse effects of engineered nanoparticles on human health due to their increasing use in commercial and medical applications. Silica nanoparticles (SiNPs) are one of the most widely used nanoparticles in industry and have been formulated for cellular and non-viral gene delivery in the central nerve system. However, the potential neurotoxicity of SiNPs remains largely unclear. In this study, we investigated the cellular uptake of SiNPs in human SK-N-SH and mouse neuro2a (N2a) neuroblastoma cells treated with 10.0 μg/ml of 15-nm SiNPs for 24 h by transmission electron microscopy. We found that SiNPs were mainly localized in the cytoplasm of the treated cells. The treatment of SiNPs at various concentrations impaired the morphology of SK-N-SH and N2a cells, characterized by increased number of round cells, diminishing of dendrite-like processes and decreased cell density. SiNPs significantly decreased the cell viability, induced cellular apoptosis, and elevated the levels of intracellular reactive oxygen species (ROS) in a dose-dependent manner in both cell lines. Additionally, increased deposit of intracellular β-amyloid 1-42 (Aβ(1-42)) and enhanced phosphorylation of tau at Ser262 and Ser396, two specific pathological hallmarks of Alzheimer's disease (AD), were observed in both cell lines with SiNPs treatment. Concomitantly, the expression of amyloid precursor protein (APP) was up-regulated, while amyloid-β-degrading enzyme neprilysin was down-regulated in SiNP-treated cells. Finally, activity-dependent phosphorylation of glycogen syntheses kinase (GSK)-3β at Ser9 (inactive form) was significantly decreased in SiNP-treated SK-N-SH cells. Taken together, these data demonstrated that exposure to SiNPs induced neurotoxicity and pathological signs of AD. The pre-Alzheimer-like pathology induced by SiNPs might result from the dys-regulated expression of APP/neprilysin and activation of GSK-3β. This is the first study with direct evidence indicating that in addition to neurotoxicity induced by SiNPs, the application of SiNPs might increase the risk of developing AD.
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China.
Xifei
X
Yang
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China.
Chun'e
C
He
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China; Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
Jie
J
Li
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China.
Hongbin
H
Chen
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China.
Quan
Q
Ma
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China.
Xiaojing
X
Sui
College of Life Sciences, Shenzhen University, Nanhai Ave 3688, Nanshan District, Shenzhen 518060, China.
Shengli
S
Tian
College of Life Sciences, Shenzhen University, Nanhai Ave 3688, Nanshan District, Shenzhen 518060, China.
Ming
M
Ying
Laboratory of Molecular Biology, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China.
Qian
Q
Zhang
The Research Center of Neurodegenerative Diseases and Aging, Medical College of Jinggangshan University, 28 Xueyuan Road, Qingyuan District, Ji'an 343009, China.
Yougen
Y
Luo
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China.
Zhixiong
Z
Zhuang
Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Nanshan District, Shenzhen 518055, China. Electronic address: junii8@126.com.
Jianjun
J
Liu
D000544:Alzheimer Disease / Q000139:chemically induced / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000633:toxicity*; D016875:tau Proteins / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D016875:tau Proteins; D012822:Silicon Dioxide; D038362:Glycogen Synthase Kinase 3
Alzheimer's disease (AD); Neurotoxicity; Silica nanoparticles (SiNPs); Tau; β amyloid (Aβ)