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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 張芳嘉(Fang-Chia Chang) | |
| dc.contributor.author | Mi Lee | en |
| dc.contributor.author | 李宓 | zh_TW |
| dc.date.accessioned | 2022-11-25T06:33:29Z | - |
| dc.date.copyright | 2021-08-18 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-07-19 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82194 | - |
| dc.description.abstract | "阿茲海默症 (Alzheimer’s disease, AD) 為神經退化性疾病，其特徵伴隨著有病理學標誌物包含類澱粉斑塊 (Amyloid-beta plaques, Aβ) 和神經纖維纏結 (Neurofibrillary tangles, NFT)的堆積、神經元的丟失以及認知功能漸進式退化。阿茲海默症可被歸類為偶發型阿茲海默症 (Sporadic AD, sAD)以及家族性阿茲海默症 (Familial AD, fAD)。最主要的阿茲海默症病例為偶發型居多，其罹患原因可源於許多因素，包含環境以及老化問題。然而家族性阿茲海默症佔所有病例數少於百分之一。鏈脲佐菌素 (Streptozotocin, STZ) 為一類葡萄糖胺類化合物，近年來被發現以腦室內注射 (intra-cerebroventricular injection, icv) STZ可在齧齒類中樞神經系統干擾胰島素受體相關訊息傳遞路徑，並模擬類似於阿茲海默症的病理學癥狀。除了腦室內注射STZ可用來誘導偶發型阿茲海默症，海馬迴 (intra-hippocampal, ih)內注射Aβ1-42片段同樣也能表現出許多人類阿茲海默症的面向。腺苷 (Adenosine) 在中樞神經系統中能透過神經迴路來調節神經生理功能，包含參與學習及記憶能力還有睡眠的調控。平衡腺苷通道蛋白第一型 (Equilibrative nucleoside transporter 1, ENT1) 為調節胞內外腺苷濃度重要的穿膜通道蛋白。在本研究中，icv-STZ以及ih- Aβ1-42 被使用來建立可靠的偶發型動物模式，並用來評估 ENT1 抑制劑的效用。注射藥物過後十四天，在腹側海馬迴中有Aβ以及磷酸化tau蛋白累積。重複給予ENT1抑制劑後，在sAD小鼠海馬迴內一氧化氮 (Nitric oxide, NO)過高、活化態凋亡蛋白酶第三型 (cleaved-caspase 3)、組蛋白 (H2A histone family member X) 磷酸化程度以及DNA絲氨酸/蘇氨酸蛋白激酵素(DNA-dependent serine/threonine protein kinase, DNA-PKcs)的活性皆被校正回正常水準。另外在基底前腦medial septum-diagonal band of Broca (MS/DB) 核區內膽鹼神經元 (cholinergic neuron) 的丟失同樣也被ENT1 抑制劑減緩。新穎物體辨識 (Novel object recognition, NOR) 以及莫氏水迷津 (Morris water maze, MWM) 的結果顯示，學習和記憶能力的缺損能因為ENT1抑制劑而被改善。腦電圖分析結果表明，小鼠在Aβ以及STZ誘導後出現睡眠障礙，然而因為ENT1抑制劑而提高的胞外腺苷濃度則有助於改善睡眠恆定。總結以上結果，ENT1抑制劑應用於本研究中的疾病動物模式提供了潛在新穎的偶發型阿茲海默症治療方向。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T06:33:29Z (GMT). No. of bitstreams: 1 U0001-1507202113404600.pdf: 2949327 bytes, checksum: e743e4b7fe387bff206b8720c378a4ac (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 致謝 II 中文摘要 III 英文摘要 V 目錄 VII 圖目錄 X 1. Introduction 1 2. Specific aims 11 3. Materials and methods 12 3.1 Reagents and drugs 12 3.2 Animals 12 3.3 Implantation of cannula and electroencephalography (EEG) 13 3.4 Electroencephalography recording and sleep analysis 14 3.5 Experimental designs 15 3.6 Behavioral assays 16 3.6.1 Novel object recognition (NOR) 16 3.6.2 Morris water maze (MWM) 17 3.7 Brain tissue preparation 19 3.8 Western blot 20 3.9 Immunofluorescence assay 21 3.10 Griess assay 22 3.11 Statistical analysis 22 4. Results 24 4.1 icv-STZ with ih-Aβ1-42 caused amyloid-beta plaques accumulation in the dorsal-hippocampus 24 4.2 STZ and Aβ1-42-infused-mice exhibited tau hyperphosphorylation in the hippocampus 26 4.3 Effects of the ENT1 inhibitor on expression of nitric oxide in icv-STZ and ih-Aβ1-42-infused mice 28 4.4 Effects of the ENT1 inhibitor on the expression of DNA damage marker and apoptosis in icv-STZ and ih-Aβ1-42-infused mice 30 4.5 Effects of the ENT1 inhibitor on the activation of DNA-PKcs in the hippocampus in icv-STZ and ih-Aβ1-42-infused mice 33 4.6 Effects of the ENT1 inhibitor on cholinergic neuronal loss in the MS/DB in icv-STZ and ih-Aβ1-42-infused mice 35 4.7 Effects of the ENT1 inhibitor on icv-STZ and ih-Aβ1-42-induced impairment of recognition memory in sAD mice 39 4.8 Effects of the ENT1 inhibitor on learning and spatial memory in icv-STZ and ih-Aβ1-42-induced mice 42 4.9 Effects of the ENT1 inhibitor on icv-STZ and ih- Aβ1-42-induced sleep disruption 46 5. Discussion 54 6. Conclusion 64 References 65 Fig. 1 Flow chart of experimental protocol. 16 Fig. 2 Experimental protocol of NOR. 17 Fig. 3 The icv-STZ with ih-Aβ1-42 resulted in amyloid-beta plaque accumulation in the dorsal hippocampus of mice. 25 Fig. 4 The effects of icv-STZ and ih-Aβ1-42 on tau protein phosphorylation. 27 Fig. 5 The ENT1 inhibitor attenuated the levels of nitric oxide in the hippocampal region in STZ and Aβ1-42-infused mice. 29 Fig. 6 ENT1 inhibitor alleviated the DNA damage and apoptosis in hippocampus in icv-STZ and ih-Aβ1-42-infused mice. 31 Fig. 7 Oral administration of the ENT1 inhibitor reversed the activity of phospho-DNA-PKcs in the hippocampus in icv-STZ and ih-Aβ1-42-infused mice. 34 Fig. 8 Oral-administration of the ENT1 inhibitor alleviated the loss of cholinergic neurons in MS/DB in icv-STZ and ih-Aβ1-42-infused mice. 37 Fig. 9 Oral-administration of the ENT1 inhibitor prevented the cognitive ability decline in icv-STZ and ih-Aβ1-42-infused mice. 41 Fig. 10 Oral-administration of the ENT1 inhibitor prevented the learning and spatial memory decline in icv-STZ and ih-Aβ1-42-infused mice. 45 Fig. 11 Oral administration of the ENT1 inhibitor diminished the disruptions of sleep pattern induced by icv-STZ and ih-Aβ1-42. 52 | |
| dc.language.iso | en | |
| dc.subject | ENT1抑制劑 | zh_TW |
| dc.subject | 偶發型阿茲海默症 | zh_TW |
| dc.subject | 類澱粉蛋白 | zh_TW |
| dc.subject | 鏈脲佐菌素 | zh_TW |
| dc.subject | 腺苷 | zh_TW |
| dc.subject | sporadic Alzheimer’s disease (sAD) | en |
| dc.subject | streptozotocin (STZ) | en |
| dc.subject | adenosine | en |
| dc.subject | ENT1 inhibitor | en |
| dc.subject | amyloid-beta (Aβ) | en |
| dc.title | ENT1抑制劑於鏈脲佐菌素及β-類澱粉蛋白斑塊誘導之偶發型阿茲海默症作用評估 | zh_TW |
| dc.title | The assessments of equilibrative nucleoside transporter 1 inhibitor in icv-STZ with ih-Aβ1-42-induced sporadic Alzheimer's disease | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 蕭逸澤(Yi-Tse Hsiao) | |
| dc.contributor.oralexamcommittee | 尹珮璐(Hsin-Tsai Liu),陳儀莊(Chih-Yang Tseng),周碩彬 | |
| dc.subject.keyword | 偶發型阿茲海默症,類澱粉蛋白,鏈脲佐菌素,腺苷,ENT1抑制劑, | zh_TW |
| dc.subject.keyword | sporadic Alzheimer’s disease (sAD),amyloid-beta (Aβ),streptozotocin (STZ),adenosine,ENT1 inhibitor, | en |
| dc.relation.page | 72 | |
| dc.identifier.doi | 10.6342/NTU202101485 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-07-19 | |
| dc.contributor.author-college | 獸醫專業學院 | zh_TW |
| dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
| dc.date.embargo-lift | 2026-07-01 | - |
| Appears in Collections: | 獸醫學系 | |
Files in This Item:
| File | Size | Format | |
|---|---|---|---|
| U0001-1507202113404600.pdf Restricted Access | 2.88 MB | Adobe PDF | View/Open |
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