ASSESSING THE POTENTIAL RISK OF SILICA NANOPARTICLE EXPOSURE IN DEVELOPING ALZHEIMER'S-LIKE PATHOLOGY

Abstract

Silica nanoparticles (SiNPs) are among nanomaterials with the highest total output in the 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. CCK-8 assay was performed to assess cell viability. Transmission electron microscopy (TEM) was used to reveal the distribution of SiNPs. Hoech st33342/PI and TUNEL staining was performed to measure apoptosis. Immunofluorescent staining was performed to measure the change of Aβ 1-42. Western-blot analysis was performed to measure the phosphorylation of tau. In this study, we showed by transmission electron microcopy uptake of SiNPs by human SK-N-SH and mouse neuro2 a neuroblastoma cells treated with 10.0 μg/ml of 15-nm SiNPs for 24h. SiNPs were mainly localized in the cytoplasm of the cells. The treatment of SiNPs of various concentrations impaired the morphology ofSK-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-amyloid1-42(Aβ 1-42) and enhanced phosphorylation of tau at Ser262 and Ser396, two specific pathological hallmarks of Alzheimer's disease (AD), were observed in SK-N-SH and N2a cells treated with SiNPs. Concomitantly, the expression of amyloid precursor protein (APP) was up-regulated, while amyloid-β-degrading enzyme neprilysin was down-regulated in SiNP-treated cells. Activity-dependent phosphorylation of glycogen syntheses kinase(GSK)-3β at Ser9 (in active 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. Thepre-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 providing evidence indicating that in addition to neurotoxicity induced by SiNPs, the application of SiNPs might increase the risk of developing AD. Acknowledgements: This work was supported by the Upgrade Scheme of Shenzhen Municipal Key Laboratory (ZDSY20120615085804889,CXB201005260068A). Keyword: Silica nanoparticles (SiNPs); Neurotoxicity; Alzheimer'sdisease(AD); βamyloid(Aβ); Tau.