From the Cover: Comparative Proteomics Reveals Silver Nanoparticles Alter Fatty Acid Metabolism and Amyloid Beta Clearance for Neuronal Apoptosis in a Triple Cell Coculture Model of the Blood–Brain Barrier

Abstract

Silver nanoparticles (AgNPs) enter the central nervous system through the blood-brain barrier (BBB). AgNP exposure can increase amyloid beta (Aβ) deposition in neuronal cells to potentially induce Alzheimer's disease (AD) progression. However, the mechanism through which AgNPs alter BBB permeability in endothelial cells and subsequently lead to AD progression remains unclear. This study investigated whether AgNPs disrupt the tight junction proteins of brain endothelial cells, and alter the proteomic metabolism of neuronal cells underlying AD progression in a triple cell coculture model constructed using mouse brain endothelial (bEnd.3) cells, mouse brain astrocytes (ALT), and mouse neuroblastoma neuro-2a (N2a) cells. The results showed that AgNPs accumulated in ALT and N2a cells because of the disruption of tight junction proteins, claudin-5 and ZO-1, in bEnd.3 cells. The proteomic profiling of N2a cells after AgNP exposure identified 298 differentially expressed proteins related to fatty acid metabolism. Particularly, AgNP-induced palmitic acid production was observed in N2a cells, which might promote Aβ generation. Moreover, AgNP exposure increased the protein expression of amyloid precursor protein (APP) and Aβ generation-related secretases, PSEN1, PSEN2, and β-site APP cleaving enzyme for APP cleavage in ALT and N2a cells, stimulated Aβ40 and Aβ42 secretion in the culture medium, and attenuated the gene expression of Aβ clearance-related receptors, P-gp and LRP-1, in bEnd.3 cells. Increased Aβ might further aggregate on the neuronal cell surface to enhance the secretion of inflammatory cytokines, MCP-1 and IL-6, thus inducing apoptosis in N2a cells. This study suggested that AgNP exposure might cause Aβ deposition and inflammation for subsequent neuronal cell apoptosis to potentially induce AD progression.

Mass spectrometry-based proteomics for system-level characterization of biological responses to engineered nanomaterials

“…Moreover, perturbation in oxidative phosphorylation and fatty acid metabolism were also observed in mouse neuroblastoma N2a exposed to silver ENMs [7]. A similar observation was made in human monocyte THP-1 cells treated with gold ENM, in which proteins involved in energy metabolism such as glucose-6-phosphate dehydrogenase and long-chain fatty acid-CoA ligase 1 were up-regulated [73].…”

“…Applications of ENMs in diagnostic assays and drug delivery systems for treatment of human diseases have also increased substantially in the last decade [3–5]. However, the potential risk to human health due to the prevalent use and potential exposure to many kinds of ENMs through ingestion, inhalation, or even penetration via the skin is also an important concern [6,7]. …”

Comparative proteomic analysis of silver nanoparticle effects in human liver and intestinal cells

“…We have studied effects in intestinal Caco‐2 cells (Oberemm et al, ), while Georgantzopoulou and colleagues have studied the effects of nanoparticulate and ionic silver on a Caco‐2/HT29‐MTX co‐culture (Georgantzopoulou et al, ). Additional analyses have been carried out with the human intestinal cell line LoVo (Miethling‐Graff et al, ; Verano‐Braga et al, ) and some other non‐liver cell lines (Driessen et al, ; Huang et al, ; Lin et al, ). In essence, these proteomic analyses confirmed the important role of reactive oxygen species and oxidative stress in silver toxicity, and provided evidence for inflammatory responses, modulation of cell cycle and cell death, as well as alterations in post‐translational protein modification and energy metabolism.…”

“…Fatty acid metabolism is a toxicologically relevant cellular function, which was predicted to be altered by silver in our study, but this molecular pathway did not explicitly pop up in previous transcriptome analyses (Kawata et al, ; Sahu et al, ). However, studies in other cell lines have clearly shown an influence of nanosilver on mitochondrial function and fatty acid metabolism at the mRNA, protein and metabolite levels (Chen et al, ; Lin et al, ; Oberemm et al, ).…”

“…shown an influence of nanosilver on mitochondrial function and fatty acid metabolism at the mRNA, protein and metabolite levels (Chen et al, 2014;Lin et al, 2017;Oberemm et al, 2016).…”