奈米粒子(nanoparticles; NPs)為粒徑小於100 nm的分子，具有高度沉積性，能經由血液循環系統累積於身體器官。隨著奈米科技的發展，將銀奈米化後產生的奈米銀粒子(silver nanoparticles; AgNPs)，由於表面積大幅增加且具有抗菌性，廣泛應用於生活用品中，如含銀衣物、化妝品、衛生用品及食品容器，使得人體暴露於奈米物質可能造成之健康風險大幅提升。已有研究指出經呼吸系統進入之NPs，可由血液循環通過血腦屏障，進入腦及中樞神經系統中，造成發炎反應，可能誘發神經退化性疾病，如阿茲海默症(Alzheimer's disease; AD)。
本研究藉由小鼠腦部調控細胞行為的星狀膠質細胞(murine brain ALT astrocytes)、調控發炎反應的微膠質細胞(microglial BV-2 cells)，及調控神經訊號傳遞的腦神經瘤細胞 (neuroblastoma Neuro2a (N2a) cells)暴露3-5 nm AgNPs，探討AgNPs可能誘發發炎反應及神經退化性疾病相關基因表現之效應。研究結果顯示，在偏光顯微鏡下可以觀察到暴露12.5 µg/mL AgNPs會通過小鼠神經N2a細胞膜進入細胞內，增加interleukin-1β (IL-1β)分泌。此外，免疫螢光染色能偵測到AgNPs暴露會促使類澱粉蛋白(β-amyloid protein; Aβ)沈積。高濃度AgNPs (5-12.5 µg/mL)暴露會增加ALT細胞及BV-2細胞主要調控發炎反應和氧化還原相關之C-X-C motif chemokine 13 (CXCL13)、macrophage receptor with collagenous structure (MARCO)及glutathione synthetase (GSS)基因表現。隨AgNPs暴露濃度升高，在ALT、BV-2及N2a細胞也會誘發AD之沉積澱粉樣前驅蛋白(amyloid precursor protein; APP)基因表現量，並降低分解Aβ的腦啡肽酶neprilysin (NEP)及運送Aβ的接收器low-density lipoprotein receptor (LDLR)基因表現量。
利用Kyoto Encyclopedia of Genes and Genomes (KEGG)資料庫和Cytoscape軟體，分析Phalanx Mouse OneArray®基因晶片結果，發現AgNPs暴露會影響調控各種不同基因功能路徑的基因表現。在調控細胞行為及生長訊號的focal adhesion路徑中，AgNPs促使上游Ras protein-specific guanine nucleotide-releasing factor 1 (RasGRF1)基因表現上升，下調B-cell lymphoma 2 (BCL2)表現量，可能導致細胞凋亡。在調控發炎因子及細胞活化的cytosolic DNA sensing路徑中，AgNPs會降低three-prime repair exonuclease 1 (TREX1)表現量，調控下游interferon regulatory factor 7 (IRF7)基因表現下降，可能造成發炎相關的細胞激素釋放，引起發炎反應。與細胞反應、週期相關的MAPK路徑，AgNPs藉由影響上游基因growth arrest and DNA-damage-inducible alpha (GADD45α)過度表現，使調控神經細胞生長及分化功能的protein tyrosine phosphatase receptor-type R (PTPRR)表現量下調，影響小腦運動功能的協調能力。本研究也發現在AD致病路徑中之presenilin-1 (PSEN1)和presenilin-2 (PSEN2)基因，會因AgNPs暴露濃度增加而降低其表現量，可能引起鈣離子平衡失調並導致神經元突觸的功能障礙。此外，AgNPs暴露使得這三株小鼠神經細胞會共同參與免疫反應，促使interferon regulatory factor 1 (IRF1)基因表現，造成發炎相關細胞激素釋放及DNA損傷。
本研究顯示AgNPs會進入小鼠腦神經細胞內，引起發炎反應，促使Aβ蛋白產生，而且改變發炎反應、氧化壓力、細胞行為、發炎因子釋放、細胞週期、免疫反應及AD致病之相關基因表現。因此，根據本研究結果推測，暴露AgNPs可能會誘發神經退化性疾病之病程。

Nanoparticles are particles between 1 and 100 nanometers in size able to highly deposit in body organs by circulatory system. Silver nanoparticles (AgNPs) have antibacterial characteristics, and currently are applied in Ag-containing clothes, cosmetics, wound dressing, air-freshener sprays, water disinfectant, sunscreens, hygiene products and food containers. Human would suffer health risk due to the widespread usage of AgNPs. AgNPs can cross through blood brain barrier (BBB) to enter into the brain and central nervous system (CNS), and might induce inflammatory response for the progression of neurodegenerative disease such as Alzheimer’s disease (AD).
This study investigated the potential effects of 3-5 nm AgNPs on gene expression of inflammation and neurodegenerative disorder in murine brain ALT astrocytes, microglial BV-2 cells and neuron N2a cells. ALT, BV-2 and N2a cells respectively regulate cell behavior, inflammatory response and signal transduction. The results found AgNPs can cross the cell membrane of N2a cells detectable under a polarizing microscope, and obviously increase interleukin-1β (IL-1β) secretion. Additionally, immunofluorescence images showed amyloid-β (Aβ) plaques for pathological feature of AD deposited in neural cells after AgNPs exposure. ALT and BV-2 cells mainly corresponded to the increased gene expression of C-X-C motif chemokine 13 (CXCL13), macrophage receptor with collagenous structure (MARCO) and glutathione synthetase (GSS) for inflammatory response and oxidative stress after 5, 10 and 12.5 µg/mL AgNPs exposure. AgNPs exposure induced the gene expression of amyloid precursor protein (APP), and reduced amyloid-degrading enzyme neprilysin (NEP) and Aβ transporter low-density lipoprotein receptor (LDLR) underlying the potential effect on Aβ deposition in ALT, BV-2 and N2a cells.
In the analysis of Phalanx Mouse OneArray® chip data, Kyoto Encyclopedia of Genes and Genomes (KEGG) database and Cytoscape software were used to identify the alternation of gene expression in various pathways for neural cells exposed AgNPs. In focal adhesion pathway regulating cell behavior and growth signaling, AgNPs might induce the gene expression of ras protein-specific guanine nucleotide-releasing factor 1 (RasGRF1) and reduce the downstream B-cell lymphoma 2 (BCL2) gene potentially to cause cell death. AgNPs exposure would reduce the gene expression of three-prime repair exonuclease 1 (TREX1) and decrease interferon regulatory factor 7 (IRF7) to release inflammatory related cytokines in cytosolic DNA sensing for inflammation and cellular activation. In MAPK pathway relevant to cellular response and cell cycle, AgNPs could induce growth arrest and DNA-damage-inducible alpha (GADD45α) gene overexpression and reduce downstream protein tyrosine phosphatase receptor-type R (PTPRR) gene to interfere with neuron growth and differentiation, cerebellum motor coordination and balance skills. The findings of this study presented AgNPs exposure decreased presenilin-1 (PSEN1) and presenilin-2 (PSEN2) gene expression in dose-dependent manners to disrupt calcium homeostasis and presynaptic dysfunction for AD development. In exposure to AgNPs, the three mouse neural cells were all involved in the immune response to induce interferon regulatory factor 1 (IRF1) gene expression underlying inflammatory cytokine release and DNA damage.
This study found that AgNPs can enter mouse neural cells to evoke inflammation and accelerate the Aβ plague formation. AgNPs exposure obviously altered the gene expression of inflammatory response, oxidative stress, cell behavior, cytokines release, cell cycle, immune effect and AD related genes. These findings suggested that AgNPs exposure potentially caused neurodegenerative disease progression.

Table of contents
Chapter 1 Introduction 1
1.1 Silver nanoparticles 1
1.2 Exposure routes of AgNPs 2
1.3 The effect of AgNPs 2
1.4 AgNPs induce neurotoxicity 4
1.5 Alzheimer’s disease 5
1.6 Neural cells 6
1.7 Gene expression in neural cells 7
Chapter 2 Aim of this study 10
Chapter 3 Material and Method 12
3.1 Cell culture and exposure 12
3.2 Cell proliferation of neural cells 13
3.3 Cytokine assay of IL-1β 13
3.4 RNA extraction 14
3.5 Polarizing microscope 15
3.6 Immunofluorescence detection of Aβ protein 15
3.7 Reverse transcription polymerase chain reaction and quantitative real-time PCR 16
3.8 Gene expression profiling analysis 19
3.9 Gene ontology analysis 20
3.10 KEGG pathway analysis 20
3.11 Cytoscape analysis 21
3.12 Statistical analysis 22
Chapter 4 Results 23
4.1 Morphology and cellular uptake of mouse neural cells in exposure to AgNPs… 23
4.2 Cytotoxicity of AgNPs in mouse neural cells 25
4.3 Cytokine secretion of mouse neural cells in exposure to AgNPs 26
4.4 Immunofluorescence staining of Aβ protein in N2a cells 27
4.5 Gene expression of inflammatory and AD related genes in mouse neural cells in exposure to AgNPs 32
4.6 Gene expression change with AgNPs treatment 34
4.7 GO term and KEGG pathway of differentially expressed genes in mouse neural cells after AgNPs treatment 36
4.8 Cytoscape analysis of differentially expressed genes in mouse neural cells after AgNPs treatment 45
4.9 Gene expression of RasGRF1 and BCL2 in AgNPs-treated ALT cells 54
4.10 Gene expression of TREX1 and IRF7 in AgNPs-treated BV-2 cells 56
4.11 Gene expression of GADD45α and PTPRR in AgNPs-treated N2a cells 58
4.12 Analysis of the selected gene expression relevant to AD pathway for AgNPs-treated cells 60
4.13 The number of DEGs after 5, 10 and 12.5 µg/mL AgNPs exposure in ALT, BV2 and N2a cells 63
4.14 Cytoscape analysis of Alzheimer’s disease and immune effect after AgNPs exposure in ALT, BV-2 and N2a cells 67
4.15 Analysis of Cytoscape in AgNPs-treated ALT, BV-2 and N2a cells 71
Chapter 5 Discussion 75
5.1 AgNPs exposure induced inflammatory response in mouse neural cells 76
5.2 AgNPs exposure lead to Aβ amyloid plaques deposition 77
5.3 AgNPs exposure changed gene expression in mouse neural cells 78
5.4 The potential mechanism of AD pathogenesis in mouse neural cells exposure to AgNPs 84
Chapter 6 Conclusion 86
Chapter 7 References 87

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