Open access peer-reviewed chapter

Impact of Silver Nanoparticles on Neurodevelopment and Neurodegeneration

Written By

Yiling Hong

Submitted: 15 September 2021 Reviewed: 22 November 2021 Published: 07 February 2022

DOI: 10.5772/intechopen.101723

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Neurotoxicity - New Advances

Edited by Suna Sabuncuoglu

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Silver nanoparticles (AgNPs) are one of the most highly commercialized nanoparticles, having been used extensively as an antimicrobial agent in cosmetics, textiles, foods, and the treatment of diseases. However, the impact of AgNPs on human mental health has not yet been well characterized. Using the human pluripotent stem cell (hPSC) neuronal differentiation cellular model to assess AgNPs neurotoxicity has several benefits. First, hPSCs neuronal differentiation process can faithfully recapitulate stages of neural development from neuronal progenitors to mature neurons which can provide an excellent platform for neurodevelopment and neurodegeneration toxicity testing. Furthermore, it can limit the amount of animal use for toxicity studies. With this cellular model, we examined citrate-coated AgNPs (AgSCs) and Polyvinylpyrrolidone-coated (AgSP) mediated neurotoxicity. Our results suggested that AgNP induced neurotoxicity exhibited a coating and dose-dependent manner. AgSC had high neurotoxicity compared with AgSP. AgSC significantly up-graduated Metallothionein (1F, 1E, 2A) proteins, a metal-binding protein that plays an essential role in metal homeostasis, heavy metal detoxification, and cellular anti-oxidative defense. Transcriptome analysis indicated that AgSC inhibited neurogenesis and axon guidance, promoted gliogenesis and neuronal apoptosis through oxidative stress. Supplementation with ascorbic acid can act as an antioxidant to attenuate AgNP-mediated neurotoxicity.


  • silver nanoparticles (AgNP)
  • human pluripotent stem cell-derived neuronal network
  • transcriptome analysis
  • oxidative stress
  • neurogenesis and gliogenesis
  • neurodegeneration

1. Introduction

Engineered nanomaterials (ENMs) are ultra-fine materials (ranging from 1 to 100 nm in length or diameter) that are currently being developed for diverse applications due to their unique optical, electrical, and thermal properties [1, 2, 3]. Among them, silver nanoparticles (AgNPs) are one of the most widely used in medical and commercial products for their unique antibacterial functions [4, 5, 6, 7, 8, 9, 10]. The AgNP market is expected to reach USD 2.45 billion by 2022 (Globe Newswire, San Francisco, 2015). Furthermore, over the next decade, Nanotechnological approaches will continue to play a vital role in neuroscience, not just in the development of highly specific and sensitive imaging probes and biosensor interfaces, but also potential tools for treatment strategies [11, 12]. For example, molecules will be nano-engineered to cross the blood-brain barrier to target specific cell or signaling systems or act as vehicles for gene delivery [13, 14].

Although the translation of nanotechnology into the treatment of human neurological disorders is very promising, the biocompatibility of these materials is still a primary concern [8]. A wealth of data demonstrates that ENMs have the potential to induce inflammation, oxidative stress, and DNA damage, which point towards potential health risks for humans, including cardiovascular diseases, pulmonary diseases, impairment of brain function, and developmental toxicity [15, 16, 17]. Recently, researchers have begun to explore the potential neurotoxicity of ENMs such as AgNPs in cellular and animal models [18, 19, 20, 21]. These studies showed that AgNPs can accumulate in the central nervous system (CNS) through the upper respiratory tract via the olfactory bulb or through crossing the blood-brain barrier, and thus induce neurodegeneration [10, 22, 23]. Furthermore, studies showed that AgNP exposure impairs neurodevelopment in PC12 cells and stem cell-derived neuronal networks and alters the expression of genes involved in neuronal function that are distinct from those of Ag+ alone, depending on size and coating [24, 25, 26].

So far, there has been limited information regarding the impact of AgNPs on neuronal development and neurodegeneration both in vivo and in vitro. hPSCs neuronal differentiation protocol evaluates the impact of AgNPs on multiple stages of differentiation ranging from neuronal progenitors to mature neuron and astrocyte networks [24, 25, 27]. This cellular model will help us to understand the mechanisms behind AgNP-mediated neuronal toxicity and identify the molecular markers to assess mental health risks associated with products containing EMNs. This book chapter is a summary of our recent studies regarding AgNP mediated neurotoxicity.


2. The impact of AgNP on neurogenesis

Neurogenesis is a series of developmental events leading to the formation of new neurons and astrocyte support cells. Neurogenesis is not only the most active process during the pre-natal stage but also happens in certain regions of the brain, such as the subgranular layer of the hippocampal dentate gyrus throughout life in mammals. Studies found that adult brains are more plasticity than previously thought. The process of neurogenesis is tightly regulated and influenced by both intrinsic genetic factors and extrinsic environmental factors. The process involves transitions from proliferation to differentiation, accompanied sequentially by the expression of the transcriptional factors such as Pax6, Tbr2, NeuroD, and Tbr1 [28]. If these gene expressions are altered, the neurogenesis events will be disrupted, which can lead to neuropsychiatric diseases such as anxiety, learning and memory, and Alzheimer’s disease (AD) [29, 30].

Our study indicates that when citrate-coated AgNP (AgSC) were administered to the media during stem cell neuronal differentiation, neuronal progenitor rosettes were immunostained with neuronal progenitor markers: sex-determining region Y-box 2 (SOX2) and VI intermediate filament protein (Nestin). The results showed that AgSC exposure disrupted neuronal tube-like rosette formation and reduced neuronal progenitor population (Figure 1A). Quantification of SOX2 and Nestin relative fluorescence intensity showed that AgSC reduced SOX2 expression and increased Nestin expression in a concentration-dependent manner (Figure 1B). The alternation of the expression level of Sox2 and Nestin will change the neural progenitor fate. Furthermore, flow cytometric analysis for the population of neuronal progenitors with SOX2 and Nestin markers indicated that the percentage of SOX2+ and Nestin+ neuronal progenitors decreased from 54.3.3% to 20.9%, while SOX2 and Nestin cells which would be unable to differentiate into neurons increased from 20.19% to 47.7% at 1.0 μg/mL AgSC exposure compared to untreated sample. In contrast, SOX2 and Nestin+ progenitors, which potentially could develop into astrocytes, increased from 23.3% to 26.1% with the same treatment (Figure 2A). The ratio of Nestin+/SOX2 and Nestin+ elevated to 1.45 at 1.0 μg/mL AgSC exposure, while the control group is 0.43. Those data support our hypothesis that AgSC inhibited neurogenesis and promoted gliagenesis. Lower concentrations of AgSC (0.1 μg/mL) slightly reduced SOX2 and Nestin expression, but the impact is insignificant. Supplements of AA partially reduced the effects (Figure 1C).

Figure 1.

AgSC inhibited neurogenesis and promoted gliogenesis. A. AgSC inhibited neuronal rosette formation. Scale bar = 100 μm. B. Quantification of SOX2 and nestin relative intensities (fold of control), ratio of intensity between SOX2 and nestin from immunofluorescent staining images. C. BDAccuri C6 flow cytometer analysis the neuronal progenitor population. D. Ratio of nestin+/SOX2 and nestin+ from flow cytometry result. Data is presented as mean ± SEM, *p < 0.05, or **p < 0.01 vs. control.

Figure 2.

AgSC significantly altered gene expression A. Total DEGenes of 1.0 μg/mL AgSCs treated group compared with control group. The significant genes (P ≤ 0.05) were labeled with red color. B. Quantitative real-time PCR to examine selected genes. FOXG1, NeuroD6 and NTS were significantly down-regulated. MT1E was significantly up-regulated. Data is presented as mean ± SEM, *p < 0.05, or **p < 0.01 vs. control. C. The clustered by GO biological processes. Result was shown as –log10(P) value. D. KEGG pathway and colored with –log10 (P) value. Min overlap ≥3, p-value ≤0.01 and min enrichment ≥1.5 were used for significant enrichments [25].

To further understand the molecular mechanisms of AgSC neuronal toxicity, a transcriptome analysis was performed., Total RNA was extracted from 3 replicates of 1.0 μg/ml AgSC exposure groups and untreated control groups to make libraries for sequencing. Significant differential expression (SDE) was cut off by padj <0.05 and |log2foldChange| > = 1. Among 322 SDE genes, 134 were up-regulated and 188 were down-regulated upon AgSC exposure (Figure 2A). The topmost up-regulated genes Metallothioneins 1F; Metallothioneins 1E; Metallothioneins 2A (45, 52, and 24 times), and frizzled class receptor 10 (FZD10) (Table 1). There are four main isoforms of cysteine-rich proteins Metallothioneins (MTs) which have the capacity to bind heavy metals such as zinc, copper, selenium, cadmium, mercury, silver, through the thiol group of its cysteine residues. MTs play important roles in metal homeostasis and protect against heavy metal toxicity, DNA damage, and oxidative stress. The other up-graduated gene is FZD10, a key regulator of the WNT signaling pathway. FZD10 plays acritical role in the neuronal pattern specification process, gliagenesis, and neurite outgrowth [31]. In addition, transcriptional factors NeuroD6, FOXG1, and NTS are among the top 20 significantly down-regulated genes (Table 2). Those genes play an important role in regulating neuronal differentiation, synaptogenesis, and axon extension during brain development [32]. The selected genes MT1E, NeuroD6, FOXG1, and NTS mRNA expression levels were examined with qPCR, respectively, and confirmed by RNA-seq data (Figure 2B).

Gene NAMElog2FoldChange
Metallothionein 1F (MT1F)5.733703827
Frizzled class receptor 10 (FZD10)5.63545845
Metallothionein 1E (MT1E)5.55542047
Vestigial like family member 3 (VGLL3)5.257650459
Pentraxin 3 (PTX3)5.249022406
Metallothionein 2A (MT2A)4.634538775
Cyclin O (CCNO)4.614228599
FZD10 antisense RNA 1 (head to head) (FZD10-AS1)3.906526795
Canopy FGF signaling regulator 1 (CNPY1)3.102452269
NAD(P)H quinone dehydrogenase 1 (NQO1)2.932494502
Sodium voltage-gated channel beta subunit 4 (SCN4B)2.863730164
Transcription factor AP-2 beta (TFAP2B)2.822828878
Zic family member 1 (ZIC1)2.792907219
Actin, alpha 2, smooth muscle, aorta (ACTA2)2.779703608
Actin, gamma 2, smooth muscle, enteric (ACTG2)2.726196918
Alpha-2-macroglobulin (A2M)2.584555887
Crumbs 2, cell polarity complex component (CRB2)2.561792956
Zic family member 4 (ZIC4)2.479236853
Neuronal pentraxin 2 (NPTX2)2.443739583
Protein tyrosine kinase 2 beta (PTK2B)2.421852257
Vasoactive intestinal peptide receptor 2 (VIPR2)2.404813991
Collagen type I alpha 2 chain (COL1A2)2.330235258
Zinc finger DHHC-type containing 22 (ZDHHC22)2.286038754
Iroquois homeobox 1 (IRX1)2.283963197
EF-hand and coiled-coil domain containing 1 (EFCC1)2.280818988

Table 1.

AgSC mediated up-graduated differential expressed genes.

Gene namelog2FoldChange
CREBATF bZIPtranscription factor (CREBZF)−3.554019527
LIM domain 7 (LMO7)−3.064914689
SRSF protein kinase 2 (SRPK2)−2.924926145
Myocyte enhancer factor 2C (MEF2C)−2.81151306
Transmembrane protease, serine 13 (TMPRSS13)−2.794313859
Neuritin1 (NRN1)−2.770934839
Ring finger protein 175 (RNF175)−2.724670035
G1 to S phase transition 2 (GSPT2)−2.674801389
Methylsterol monooxygenase 1 (MSMO1)−2.634382164
Coiled-coil domain containing 171 (CCDC171)−2.583794397
Meis homeobox 2 (MEIS2)−2.540498698
Gamma-aminobutyric acid type A receptor gamma2 subunit (GABRG2)−2.503960528
Src-like-adaptor (SLA)−2.478947195
calcium binding protein 1 (CABP1)−2.341485603
semaphorin 3F (SEMA3F)−2.336576641
fatty acid binding protein 6 (FABP6)−2.333357057
B-cell CLLlymphoma 11A (BCL11A)−2.268903493
neuronal differentiation 6 (NEUROD6)−2.2525029
neurotensin (NTS)−2.251646035
DLG associated protein 1 (DLGAP1)−2.233930932
zinc finger CCCH-type containing 15 (ZC3H15)−2.227494717
cerebellar degeneration related protein 1 (CDR1)−2.217658748
neurotensinreceptor 1 (NTSR1)−2.214928804
forkheadbox G1 (FOXG1)−2.185129942
chromosome 12 open reading frame 65 (C12orf65)−2.176721998

Table 2.

AgSC-mediated down-graduated differential expressed genes.

These significantly differentially expressed genes were analyzed by metascape ( for functional annotation clustering. Based on gene ontology analysis, in response to AgSC exposure, the most significant impact on the biological processes were regulation of neuron differentiation, brain development, synapse organization, pattern specification processes, gliogenesis, and cholesterol biosynthetic processes (Figure 2B). The KEGG analysis results showed that the affected genes were enriched in C5 isoprenoid biosynthesis, axon guidance, neuron apoptotic progress lysosomes, MAPK, WNT, Hedgehog, and Notch signaling pathways (Figure 2D). In conclusion, our data suggest that AgSCs interfere with metal homeostasis and cholesterol biosynthesis which induces oxidative stress, reduces neurogenesis and axon guidance and promotes gliogenesis and apoptosis.


3. Impact of AgNPs on neurodegeneration

Neurodegeneration is the progressive loss of structure or function of neurons due to aging, diseases, and environmental factors. Free radicals or oxidative stress may damage lipids, nucleic acids, and proteins. The brain is particularly vulnerable to oxidative stress because of its high level of protein and lipid content and low level of antioxidants [33]. Reactive oxygen species (ROS) such as superoxide (O2) and hydrogen peroxide (H2O2) are typically categorized as neurotoxic molecules associated with decreased synaptic plasticity performances in cognitive function and cell death. ROS can initiate excitotoxicity effects by inducing an intracellular calcium influx that leads to the activation of glutamate receptors and apoptosis [24]. To investigate the molecular mechanisms underlying AgNP-induced neurodegeneration, mature glutamatergic neuronal networks containing astrocytes were generated from iPSC. ROS production were examined with 20 nm citrate-coated AgNPs (AgSCs) and polyvinylpyrrolidone-coated AgNPs (AgSPs) exposure. Our results showed AgNPs-induced ROS production was coating and dose-dependent (Figure 3A). AgSCs-treated neurons produced more ROS compared to the AgSPs-treated samples.

Figure 3.

AgNP promoted ROS production, induced astrocyte activation and synapse protein loss. A. ROS was generated in a dose-dependent manner in (A–C) AgSP-treated neurons. (E–G) AgSC-treated neurons produced a higher amount of ROS compared to (D) the untreated neurons (ctrl). (H) the inset image of hGNs treated with 5 mg/ml AgSC showed the interneuronal accumulation of ROS. Scale bar 100 mM. B. Immunofluorescent staining images showed AgSC promoted astrocyte activation. C. Effect of AgSC on the excitatory synaptic protein, vGlu1 and PSD95 expression. The co-localization of vGlut1(red) and PSD95 (green) in the controls. Exposure to AgSC (5 mg/ml) significantly diminished the vGlut1and PSD95 expression and co-localization [24, 27].

We examined our hypothesis, stating that AgNPs-induced ROS will promote astrocyte activation and neuronal cell death. Astrocytes are the most numerous neuroglial cells in the central nervous system (CNS). Astrocyte vital functions include blood-brain barrier formation, providing structural and metabolic support, and regulating synaptic transmission and water transport [34, 35]. Astrocytes are sensitive to environmental changes. Under the chronic stress condition, astrocytes will undergo significant structural remodeling which reduces process length, branching, and density length [36]. Our results indicated that 0.1 μg/ml dose AgSC exposure increased the number of GFAP positive astrocytes for neuronal protection. At high doses, 5.0 μg/ml AgSC exposure altered astrocyte morphology and induced astrocyte activation. Furthermore, we examined how AgSCs affect synaptic structural and functional components. Neurons were double-stained for the presynaptic vesicle membrane protein Synaptophin (Syn) and the postsynaptic marker PSD-95 (Figure 3B). Untreated control neurons showed extensive neuritis processes co-localized between Syn and PSD-95 (Figure 3B). Exposure with AgSCs at 1.0 and 5.0 μg/mL drastically reduced Syn and PSD-95 expression and their co-localization.

We further investigated the signaling cascade involved in AgNP mediated neurodegeneration with different coatings. Glutamate receptor N-methyl-D-aspartate receptor (NMDAR) plays a key role in synaptic plasticity, which is linked to a form of long-term depression (LTD) as well as neuron survival. The dysregulation of NMDAR in neurons will trigger an apoptosis-associated increase in caspase-3 activity. The immunoblotting results showed that AgSCs reduced the expression levels of the post-glutamate receptor subunits NR2A and NR2B and increased the phosphorylation of GSK3α/βTyr216/279, whereas AgSPs had similar effects, but only at a higher concentration (5 μg/ml) (Figure 4A). GSK3 α/β phosphorylation has been shown to be associated with neural apoptosis in many neurodegenerative disorders. An increase in GSK-3β activity via GSK3α/βTyr216/279 phosphorylation can lead to Tau phosphorylation (pTau) [37, 38]. Our immunoblotting results confirmed that the AgNPs can increase GSK3 α/β phosphorylation and increase Tau phosphorylation at serine 396 in a dose-dependent manner, whereas AgSPs had no effect on Tau phosphorylation (Figure 4A). Tau is involved in the loss of neuronal dendrites and the axonal network by disrupting microtubule assembly. The result of Tau46/MAP2 double immunostaining showed that AgSC treatment caused the reduction of both protein expression and axon outgrowth (Figure 4B). Figure 4D presents a model of molecular mechanisms for AgNPs induced neurodegeneration. We suggested that phosphorylation of GSK3a/bTyr216/279could be the potential biomarker for AgNPs neurotoxicity testing.

Figure 4.

The molecular mechanisms of the AgNP induced neurotoxicity. A. Immunoblotting of glutamate receptors NR2A/B, phosphorylated GSK-3α/β and Tau46 after espousing the AgNPs at three different concentrations for 72 h. β-Actin was used as a loading control. B. Immunostaining with Tau46/Map2 indicated that the effect of AgNPs on microtubule assembly proteins expression and axon outgrowth. C. Potential molecular mechanisms underlying AgNP induced neurotoxicity [24].


4. Conclusion

In our study, neuronal progenitors, mature glutamatergic neurons, and astrocytes were derived from hPSC which were used for testing AgNPs toxicity. The results indicated that citrate-coated AgSCs significantly affected neuronal progenitor proliferation, gliagenesis, neuronal neuritis outgrowth, and cell viability due to up-graduated Metallothionein (1F, 1E, 2A) gene expression and increased ROS production. AgSPs had similar effects but only exhibited the toxicities at higher concentration exposure. In this context, the proper coating can prevent or limit the neurotoxicity associated with the AgNPs exposure. Our study indicates that stem cell-derived neuronal differentiation is an excellent cellular platform for investigating the impact of AgNPs on neuronal development and neurodegeneration and identifying biomarkers for risky assessment. In addition, this cellular model could also be used for different types of nanoparticles such as carbon-based nanoparticles, ceramic nanoparticles, metal nanoparticles, semiconductor nanoparticles, and lipid-based nanoparticles neuronal toxicity assessment in the future.



This work was supported by the National Institutes of Environmental Health Sciences (1R15 ES019298-01A1). I would like to thank Aynun Begum, Hao Li, and Neza Repar who had worked on these projects and provided the data for this book chapter.


Conflict of interest statement

The authors report no conflicts of interest.


  1. 1. Bruchez M, Moronne M, Gin P, Weiss S, Alivisatos AP. Semiconductor nanocrystals as fluorescent biological labels. Science. 1998;281:2013-2016
  2. 2. Chen X, Schluesener HJ. Nanosilver: a nanoproduct in medical application. Toxicology Letters. 2008;176(1):1-12
  3. 3. Oberdorster G, Maynard A, Donaldson K, Castranova V, Fitzpatrick J, Ausman K, et al. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Particle and Fibre Toxicology. 2005;2:8
  4. 4. Choi O, Hu Z. Size dependent and reactive oxygen species related nanosilver toxicity to nitrifying bacteria. Environmental Science & Technology. 2008;42(12):4583-4588
  5. 5. Domeradzka-Gajda KM, Nocun J, Roszak B, Janasik CD, Quarles W Jr, Wasowicz J, et al. A study on the in vitro percutaneous absorption of silver nanoparticles in combination with aluminum chloride, methyl paraben or di-n-butyl phthalate. Toxicology Letters. 2017;272:38-48. DOI: 10.1016/j.toxlet.2017.03.006
  6. 6. Kim JS, Kuk E, Yu KN, Kim JH, Park SJ, Lee HJ. Antimicrobial effects of silver nanoparticles. Nanomedicine. 2007;3:95-101
  7. 7. Westerband EI, Hicks AL. Nanosilver-enabled food storage container tradeoffs: Environmental impacts versus food savings benefit, informed by literature. Integrated Environmental Assessment and Management. 2018;14(6):769-776. DOI: 10.1002/ieam.4093
  8. 8. Wang EC, Wang AZ. Nanoparticles and their applications in cell and molecular biology. Integrative Biology. 2014;6:9-26
  9. 9. West J, Halas N. Applications of nanotechnology to biotechnology. Current Opinion in Biotechnology. 2000;11:215-217
  10. 10. Ahamed M, Alsalhi MS, Siddiqui MK. Silver nanoparticle applications and human health. Clinica Chimica Acta. 2010;411(23-24):1841-1848. DOI: 10.1016/j.cca..08.016
  11. 11. Samir TM, Mansour MM, Kazmierczak SC, Azzazy HM. Quantum dots: Heralding a brighter future for clinical diagnostics. Nanomedicine. 2012;7(11):1755-1769
  12. 12. Silva J, Bowman DM. In: Hunter R, Preedy V, editors. The Regulation of Nanomedicine. Nanomedicine in Health and Disease. Boca Raton: Science Publishers; 2012. pp. 20-42
  13. 13. Win-Shwe TT, Fujimaki H. Nanoparticles and neurotoxicity. International Journal of Molecular Sciences. 2011;12:6267-6280
  14. 14. Etame AB, Diaz RJ, O’Reilly MA, Smith CA, Mainprize TG, Hynynen K, et al. Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI-guided focused ultrasound. Nanomedicine. 2012:8(7):1133-1142
  15. 15. Colvin V. The potential environmental impacts of engineered nanomaterials. Nature Biotechnology. 2003;21:1166-1170
  16. 16. Rajanahalli P, Stuck C, Hong Y. The effects of silver nanoparticles on cell cycle progression and cell viability in mouse embryonic stem cells. Toxicology Reports. 2015;2:758-765
  17. 17. Zhu L, Dai L, Hong Y. DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. Nano Letters. 2007;7(12):3592-3579
  18. 18. Hadrup N, Loeschner K, Mortensen A, Sharma AK, Qvortrup K, Larsen EH, et al. The similar neurotoxic effects of nanoparticulate and ionic silver in vivo and in vitro. Neurotoxicology. 2012;33(3):416-423
  19. 19. Rungby J, Danscher G. Localization of exogenous silver in brain and spinal cord of silver exposed rats. Acta Neuropathologica. 1983;60(1-2):92-98
  20. 20. Rungby J, Danscher G. Neuronal accumulation of silver in brains of progeny from argyric rats. Acta Neuropathologica. 1983b;61(3-4):258-262
  21. 21. Tang J, Xiong L, Wang S, Wang J, Liu L, Li J, et al. Distribution, translocation and accumulation of silver nanoparticles in rats. Journal of Nanoscience and Nanotechnology. 2009;9(8):4924-4932
  22. 22. Hoet PH, Bruske-Hohlfeld I, Salata OV. Nanoparticles—Known and unknown health risks. Journal of Nanobiotechnology. 2004;2(1):12. DOI: 10.1186/1477-3155-2-12
  23. 23. Yang Z, Liu ZW, Allaker RP, Reip P, Oxford J, Ahmad Z, et al. A review of nanoparticle functionality and toxicity on the central nervous system. Journal of the Royal Society, Interface. 2010;7(Suppl. 4):S411-S422. DOI: 10.1098/rsif.2010.0158.focus
  24. 24. Begum AN, Aguilar JS, Elias L, Hong Y. Silver nanoparticles exhibit coating and dose-dependent neurotoxicity in glutamatergic neurons derived from human embryonic stem cells. Neurotoxicology. 2016;57:45-53. DOI: 10.1016/j.neuro.2016.08.015
  25. 25. Li H, Li QQ, Hong Y. Global gene expression signatures in response to citrate-coated silver nanoparticles exposure. Toxicology. 2021;461:152898. DOI: 10.1016/j.tox.2021.152898
  26. 26. Power C, Badireddy AR, Ryde IT, Seidler FJ, Slotkin TA. Silver nanoparticles compromise neurodevelopment in PC12 Cells: critical contributions of silver ion, particle size, coating, and composition. Environmental Health Perspectives. 2011;119:37-44
  27. 27. Repar N, Li H, Aguilar JS, Li QQ, Drobne D, Hong Y. Silver nanoparticles induce neurotoxicity in a human embryonic stem cell-derived neuron and astrocyte network. Nanotoxicology. 2018;12(2):104-116. DOI: 10.1080/17435390.2018.1425497
  28. 28. Espósito MS, Piatti VC, Laplagne DA, Morgenstern NA, Ferrari CC, Pitossi FJ, et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. The Journal of Neuroscience. 2005;25:10074-10086
  29. 29. Hevner RF, Miyashita-Lin E, Rubenstein JL. Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: Evidence that cortical and thalamic axons interact and guide each other. The Journal of Comparative Neurology. 2002;447(1):8-17. DOI: 10.1002/cne.10219
  30. 30. Martynoga B, Drechsel D, Guillemot F. Molecular control of neurogenesis: A view from the mammalian cerebral cortex. Cold Spring Harbor Perspectives in Biology. 2012;4:10. DOI: 10.1101/cshperspect.a008359
  31. 31. Levy-Strumpf N, Culotti JG. Netrins and Wnts function redundantly to regulate antero-posterior and dorso-ventral guidance in C. elegans. PLoS Genetics. 2014;10(6):e1004381. DOI: 10.1371/journal.pgen.1004381
  32. 32. Uittenbogaard M, Baxter KK, Chiaramello A. The neurogenic basic helix-loop-helix transcription factor NeuroD6 confers tolerance to oxidative stress by triggering an antioxidant response and sustaining the mitochondrial biomass. ASN Neuro. 2010;2(2):e00034. DOI: 10.1042/AN20100005
  33. 33. Ermak G, Davies KJ. Calcium and oxidative stress: From cell signaling to cell death. Molecular Immunology. 2002;38:713-721
  34. 34. Blanco-Suárez E, Caldwell AL, Allen NJ. Role of astrocyte-synapse interactions in CNS disorders. The Journal of Physiology. 2016;595(6):1903-1916. DOI: 10.1113/jp270988
  35. 35. Hacimuftuoglu AA, Tatar D, Cetin N, Taspinar F, Saruhan U, Okkay H, et al. Astrocyte/neuron ratio and its importance on glutamate toxicity: An in vitro voltammetric study. Cytotechnology. 2016;68(4):1425-1433. DOI: 10.1007/s10616-015-9902-9
  36. 36. Diniz DG, Oliveira MA, Lima CM, Fôro CA, Sosthenes MC, Bento-Torres J, et al. Age, environment, object recognition and morphological diversity of GFAP-immunolabeled astrocytes. Behavioral and Brain Functions. 2016;12(1):1-28. DOI: 10.1186/s12993-016-0111-2
  37. 37. Elyaman W, Terro F, Wong NS, Hugon J. In vivo activation and nuclear translocation of phosphorylated glycogen synthase kinase-3beta in neuronal apoptosis: links to tau phosphorylation. The European Journal of Neuroscience. 2002;15:651-660
  38. 38. Park CH, Lee BH, Ahn SG, Yoon JH, Oh SH. Serine 9 and tyrosine 216 phosphorylation of GSK-3beta differentially regulates autophagy in acquired cadmium resistance. Toxicological Sciences. 2013;135:380-389

Written By

Yiling Hong

Submitted: 15 September 2021 Reviewed: 22 November 2021 Published: 07 February 2022