簡易檢索 / 詳目顯示

研究生: 宋彥慶
Song, Yan-Qing
論文名稱: 純物質AG對阿茲海默症基因轉殖模式小鼠之影響
The effect of pure compound AG in a transgenic mice model of Alzheimer’s disease
指導教授: 林炎壽
Lin, Yenshou
學位類別: 碩士
Master
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2017
畢業學年度: 106
語文別: 中文
論文頁數: 42
中文關鍵詞: 阿茲海默症阿茲海默症模式小鼠J20小鼠中草藥
英文關鍵詞: Alzheimer’s disease (AD),, AD mouse model, J20 mouse, Chinese herbal medicine
DOI URL: https://doi.org/10.6345/NTNU202201899
論文種類: 學術論文
相關次數: 點閱:113下載:4
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 截至2015年,全世界已累計約4,800萬人罹患阿茲海默症,其為最常見之神經退化性疾病之一。然而,此疾病目前仍無法治癒,因此相關藥物的發展刻不容緩。實驗室先前建立的篩藥平台已篩選約莫12種中草藥單方,其中部分單方具有降低神經細胞去極化的潛力。研究也探索了其中一種,我們暫時將其命名為AG的純物質,在神經細胞上的作用機制。本研究即延伸AG在AD疾病模式鼠中可能的作用。小鼠分為四組:正常對應AD模式鼠以及是否給予AG,我們在小鼠皮下注射AG一個月後,肝、腎組織切片之H&E染色顯示注射溶劑之控制組與實驗組之間並無明顯改變。以阿茲海默模式小鼠 (簡稱J20小鼠) 進行行為實驗,研究發現,在開放空間測試與Y形迷宮的研究中,AG尚無逆轉J20小鼠活動亢進、短期記憶下降的作用。進一步以莫氏水迷津探討後卻發現,AG雖無法防止此種模式鼠記憶的下降,卻顯著強化了野生型小鼠之長期、短期記憶力。綜合上述,以目前給藥時程設計,尚無法確定AG對於改善記憶喪失是否有效,但對於正常小鼠之記憶行為可能有所助益,從這面向來看,AG仍具有發展成增進記憶之健康食品之潛力。

    There were approximately 48 million people developing Alzheimer’s disease (AD), one of the most common neurodegenerative diseases. Nevertheless, there is no cure for this disease so that the related drug development becomes warranted. We have previously found 6 out of 12 Chinese herbal medicines (CHMs) have the potential to ameliorate abnormally neuronal depolarization by using our drug screening platform. One of the pure compounds, temporarily named AG, has also been investigated its cellular mechanism on the primary neurons. Therefore, the efficacy of AG on AD mice model, J20, is further investigated. Mice were divided into four groups, wild type or J20 were injected with or without AG. AG were injected into mice subcutaneously for a month. The H&E staining of liver and kidney tissues showed no significant change compared to the ones injected by vehicle. AG doesn’t recover the hyperactivity and temporary memory in J20 mice assayed by using open field test and Y-maze analysis. AG can’t alleviate the memory loss in the mouse model analyzed by utilizing Morris water maze. However, AG can enhance the short-term and long-term memory on wild-type mice. Taken together, current format/timing of giving AG to mice shows inconclusive effect on memory deterioration of J20 mice. It has the benefit on enhancing memory of normal mice. Hence, it could still has the potential to develop into a dietary supplement on enhancing memory.

    目錄 I 摘要 II Abstract III 第一章 緒論 1 一、阿茲海默症 1 二、β-澱粉樣蛋白 (Aβ) 2 三、目前Aβ與神經死亡的關係 3 四、J20小鼠 3 五、中草藥 3 第二章 研究動機與目的 5 第三章 材料與實驗方法 6 一、藥品 6 二、J20小鼠基因型鑑定 6 三、小鼠之給藥處理 7 四、開放空間測試 (Open field test) 7 五、Y形迷宮測試 (Y-maze test) 8 六、莫氏水迷津測試 (Morris water maze test) 8 七、血清生化分析 9 八、小鼠灌流 (Perfusion) 及肝、腎組織H&E染色 10 九、統計分析 11 第四章 研究結果 12 一、J20小鼠基因型鑑定 12 二、生物安全性 (Biosafety) 12 (一) 小鼠體重監測 12 (二) 血清生化分析 13 (三) 肝、腎組織H&E染色 13 三、開放空間測試 (Open field test) 13 四、Y形迷宮測驗 (Y-maze test) 14 五、莫氏水迷津測試 (Morris water maze test) 14 第五章 討論 16 參考文獻 22 圖表 29

    Ahlemeyer B, Krieglstein J. Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease. Pharmacopsychiatry. 2003;36:S8-14.
    Bi M, Tong S, Zhang Z, Ma Q, Zhang S, Luo Z, Zhang Y, Li X, Wang D. Changes in cerebral glucose metabolism in patients with mild-to-moderate Alzheimer's disease: a pilot study with the Chinese herbal medicine fuzhisan. Neurosci Lett. 2011;501:35-40.
    Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2006;CD001190.
    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002;416:507-11.
    Chang WH, Chen MC, Cheng IH. Antroquinonol Lowers Brain Amyloid-β Levels and Improves Spatial Learning and Memory in a Transgenic Mouse Model of Alzheimer's Disease. Sci Rep. 2015;5:15067.
    Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puoliväli J, Lesné S, Ashe KH, Muchowski PJ, Mucke L. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007;282:23818-28.
    Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A. Amyloid β, glutamate, excitotoxicity in Alzheimer's disease: are we on the right track? CNS Neurosci Ther. 2013;19:549-55.
    Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M; Alzheimer's Disease International.Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366:2112-7.
    Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095-128.
    Gregory J Brewer & John R Torricelli. Isolation and culture of adult neurons and neurospheres. Nat Protoc. 2007;2:1490-8.
    Harris JA, Devidze N, Halabisky B, Lo I, Thwin MT, Yu GQ, Bredesen DE, Masliah E, Mucke L. Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor protein. J Neurosci. 2010;30:372-81.
    Hefti F, Goure WF, Jerecic J, Iverson KS, Walicke PA, Krafft GA. The case for soluble Aβ oligomers as a drug target in Alzheimer's disease. Trends Pharmacol Sci. 2013;34:261-6.
    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712-6.
    Huang DS, Yu YC, Wu CH, Lin JY. Protective Effects of Wogonin against Alzheimer's Disease by Inhibition of Amyloidogenic Pathway. Evid Based Complement Alternat Med. 2017;2017:3545169.
    Huang HJ, Chen WL, Hsieh RH, Hsieh-Li HM. Multifunctional Effects of Mangosteen Pericarp on Cognition in C57BL/6J and Triple Transgenic Alzheimer's Mice. Evid Based Complement Alternat Med. 2014;2014:813672.
    Kang S, Kim CH, Jung H, Kim E, Song HT, Lee JE. Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling. Neuropharmacology. 2017;113:467-479.
    Karl T, Bhatia S, Cheng D, Kim WS, Garner B. Cognitive phenotyping of amyloid precursor protein transgenic J20 mice. Behav Brain Res. 2012;228:392-7.
    Kaur S, Sharma N, Nehru B. Anti-inflammatory effects of Ginkgo biloba extract against trimethyltin-induced hippocampal neuronal injury. Inflammopharmacology. 2017.
    Kirkitadze MD, Bitan G, Teplow DB. Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J Neurosci Res. 2002;69:567-77.
    Liu P, Kong M, Liu S, Chen G, Wang P. Effect of reinforcing kidney-essence, removing phlegm, and promoting mental therapy on treating Alzheimer's disease. J Tradit Chin Med. 2013;33:449-54.
    Liu YL, Chen WT, Lin YY, Lu PH1, Hsieh SL, Cheng IH. Amelioration of amyloid-β-induced deficits by DcR3 in an Alzheimer's disease model. Mol Neurodegener. 2017;12:30.
    Luchsinger JA, Noble JM, Scarmeas N. Curr Neurol Neurosci Rep. 2007;7:366-72.
    McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;CD003154.
    Miao YC, Tian JZ, Shi J, Mao M. Effects of Chinese medicine for tonifying the kidney and resolving phlegm and blood stasis in treating patients with amnestic mild cognitive impairment: a randomized, double-blind and parallel-controlled trial. Chin J Integr Med. 2012;10:390-7.
    Murakami K, Yokoyama S, Murata N, Ozawa Y, Irie K, Shirasawa T, Shimizu T. Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer's-like phenotypes in mice. Biochem Biophys Res Commun. 2011;409:34-9.
    Palop JJ, Jones B, Kekonius L, Chin J, Yu GQ, Raber J, Masliah E, Mucke L. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A. 2003;100:9572-7.
    Parrott MD, Winocur G, Bazinet RP, Ma DW, Greenwood CE. Whole-food diet worsened cognitive dysfunction in an Alzheimer's disease mouse model. Neurobiol Aging. 2015;36:90-9.
    Pohanka M. Cholinesterases, a target of pharmacology and toxicology. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011;155:219-29.
    Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer's disease. Med Princ Pract. 2015;24:1-10.
    Shah ZA, Nada SE, Doré S. Heme oxygenase 1, beneficial role in permanent ischemic stroke and in Gingko biloba (EGb 761) neuroprotection. Neuroscience. 2011;180:248-55.
    Shuang XP, Tan ZH, Chen Q, et al. Efficacy and safety of TCM therapy for VCIND: a meta-analysis. Chin Arch Tradit Chin Med 2015;33:387–91.
    Subash S, Braidy N, Essa MM, Zayana AB, Ragini V, Al-Adawi S, Al-Asmi A, Guillemin GJ. Long-term (15 mo) dietary supplementation with pomegranates from Oman attenuates cognitive and behavioral deficits in a transgenic mice model of Alzheimer's disease. Nutrition. 2015;31:223-9.
    Sun ZK, Yang HQ, Chen SD. Traditional Chinese medicine: a promising candidate for the treatment of Alzheimer's disease. Transl Neurodegener. 2013;2:6.
    Tan MS, Yu JT, Tan CC, Wang HF, Meng XF, Wang C, Jiang T, Zhu XC, Tan L. Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis. 2015;43:589-603.
    Thies W, Bleiler L. Alzheimer's disease facts and figures. Alzheimers Dement. 2013;9:208–45.
    Todd S, Barr S, Roberts M, Passmore AP. Survival in dementia and predictors of mortality: a review. Int J Geriatr Psychiatry. 2013;28:1109-24.
    Ude C, Schubert-Zsilavecz M, Wurglics M. Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet. 2013;52:727-49.
    Vohora D, Bhowmik M. Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse. Front Syst Neurosci. 2012;6:72.
    Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Shen L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ; The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement. 2013;9:e111-94.
    Xu X, Guo L, Tian G. Diabetes cognitive impairments and the effect of traditional chinese herbs. Evid Based Complement Alternat Med. 2013;2013:649396.
    Zeng K, Li M, Hu J, Mahaman YAR, Bao J, Huang F, Xia Y, Liu X, Wang Q, Wang JZ, Yang Y, Liu R, Wang X. Ginkgo biloba extract EGb761 attenuates Hyperhomocysteinemia-induced AD like tau hyperphosphorylation and cognitive impairment in rats. Curr Alzheimer Res. 2017.
    Zhang C, Saunders AJ. Therapeutic targeting of the alpha-secretase pathway to treat Alzheimer's disease. Discov Med. 2007;7:113-7.
    Zhang SJ, Xue ZY. Effect of Western medicine therapy assisted by Ginkgo biloba tablet on vascular cognitive impairment of none dementia. Asian Pac J Trop Med. 2012;5:661-4.
    Zhao LN, Long H, Mu Y, Chew LY. The toxicity of amyloid β oligomers. Int J Mol Sci. 2012;13:7303-27.

    下載圖示
    QR CODE