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
10.0μg/ml of 15-nm SiNPs for 24h by transmission electron microcopy. 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 (Aβ1-42)
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.
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
10.0μg/ml of 15-nm SiNPs for 24h by transmission electron microcopy. 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 (Aβ1-42)
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.
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