簡易檢索 / 詳目顯示

研究生: 李欣穎
Lee, Shin-Ying
論文名稱: 降低Aβ聚集導致阿茲海默氏症之新穎甘草查爾酮A與香豆素之衍生物的藥物開發
Development of novel licochalcone A and coumarin derivatives to mitigate the amyloid beta aggregation-induced Alzheimer’s disease
指導教授: 李桂楨
Lee, Guey-Jen
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: 105
語文別: 中文
論文頁數: 94
中文關鍵詞: 阿茲海默氏症β-澱粉樣蛋白查爾酮-香豆素雜合物抗氧化抗凋亡
英文關鍵詞: Alzheimer’s disease, amyloid β, chalcone-coumarin hybrid, anti-oxidation, anti-apoptosis
DOI URL: https://doi.org/10.6345/NTNU202201995
論文種類: 學術論文
相關次數: 點閱:134下載:11
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
  • 阿茲海默氏症(Alzheimer's disease,簡稱AD),是老年癡呆症中最普遍的類型,臨床症狀包括漸進性認知功能下降以及長期記憶損傷。阿茲海默氏症的病理特徵主要可分為細胞外β-澱粉樣蛋白(β-Amyloid,簡稱Aβ)聚集形成的澱粉樣蛋白斑塊(Amyloid plaque),以及細胞內過度磷酸化tau蛋白形成的神經纖維纏結(Neurofibrillary tangles,簡稱NFTs)。Aβ斑塊造成神經細胞死亡的途徑包括氧化壓力提升、細胞外毒性、能量耗損以及細胞凋亡等,因此新Aβ聚集抑制劑的開發對於阿茲海默氏症的治療十分重要。甘草查爾酮A (Licochalcone A)及香豆素(Coumarin)為來自植物的天然化合物,具增強粒線體新生及/或抗氧化的功能。為了改善甘草查爾酮A及香豆素對阿茲海默氏症的可能治療效果,先前的研究透過化學修飾合成五種可抑制第三型小腦萎縮症polyQ蛋白聚集及幫助tau蛋白摺疊的衍生物。本研究首先以生化實驗檢測甘草查爾酮A、香豆素及五種合成衍生物捕捉自由基及抑制Aβ 聚集之能力。接著利用誘導表現Aβ-GFP之293/SH-SY5Y細胞,檢測待測化合物降低Aβ錯誤折疊及神經保護作用。在檢測的化合物中,衍生物LM-031細胞毒性最低,且具有自由基捕捉能力及Aβ聚集抑制能力,並可降低Aβ-GFP 293細胞中Aβ的錯誤折疊及相關的活性氧化物、凋亡蛋白酶-3活性,及促進Aβ-GFP SH-SY5Y細胞神經突生長。LM-031、甘草查爾酮A及香豆素可增強熱休克蛋白HSPB1表現,來增加Aβ-GFP融合蛋白溶解度,並正調控轉錄因子NRF2,來促進抗氧化反應元件依存的NQO1及GCLC表現。此外,在Aβ-GFP SH-SY5Y細胞中,LM-031、甘草查爾酮A及香豆素皆可增加與細胞存活、生長及/或抗凋亡相關因子的表現,如腦源性神經滋養因子BDNF、cAMP效應元件結合蛋白CREB、B细胞淋巴瘤蛋白-2 BCL2、胞外訊息調節激酶(ERK) 1/2、AKT絲胺酸/蘇胺酸激酶1 (AKT)等。本研究結果顯示甘草查爾酮A、香豆素及新穎查爾酮-香豆素雜合物LM-031可降低Aβ聚集及神經保護,提供臨床上阿茲海默氏症治療新的參考策略。

    關鍵字:阿茲海默氏症,β-澱粉樣蛋白,查爾酮-香豆素雜合物,抗氧化,抗凋亡。

    Alzheimer's disease (AD), the most common type of dementia in humans, is characterized as a progressive decline in cognitive function and loss of the long-term memory. The prominent pathological features of AD are aggregation of β-amyloid (Aβ) peptide in plaques and hyperphosphorylated tau protein in neurofibrillary tangles (NFTs). The Aβ deposition causes neuronal death via mechanisms including oxidative stress, excitotoxicity, energy depletion and apoptosis. Therefore, identifying novel Aβ aggregate inhibitor is essential to the disease treatment. Licochalcone A and coumarin are two natural compounds from plants with enhancing mitochondrial biogenesis and/or antioxidant activity. To improve therapeutic effects of licochalcone A and coumarin, chemical modification was applied and five licochalcone A and/or coumarin derivatives inhibiting SCA3 polyQ aggregation and reducing tau misfolding were obtained. In this study, biochemical tests were firstly used to examine the free radical scavenging and Aβ aggregation inhibition activities of licochalcone A, coumarin and the five synthetic derivatives. Tet-On Aβ-GFP 293/SH-SY5Y cells were then used to examine the ability of the tested compounds to reduce Aβ misfolding and neuroprotection. Among the tested compounds, derivative LM-031 had the lowest cytotoxicity and displayed the potentials of radical-scavenging and Aβ aggregation inhibition in biochemical tests, in addition to reducing Aβ misfolding and associated reactive oxygen species and caspase-3 activity in Aβ-GFP 293 cells and promoting neurite outgrowth in Aβ-GFP SH-SY5Y cells. LM-031, licochalcone A and coumarin enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase the solubility of Aβ-GFP fusion protein and upregulated nuclear factor erythroid 2-like factor 2 (NRF2) to promote antioxidant-responsive element-dependent NAD(P)H quinone dehydrogenase 1 (NQO1) and glutamate-cysteine ligase catalytic subunit (GCLC) expression. The expression of factors involved in cell survival, growth and anti-apoptosis, such as brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), B-cell leukemia protein 2 (BCL2), extracellular signal-regulated kinase (ERK) 1/2, and AKT serine/threonine kinase 1 (AKT) were also increased in Aβ-GFP SH-SY5Y cells by LM-031, licochalcone A and coumarin. The study results demonstrated that licochalcone A, coumarin and novel chalcone-coumarin hybrid LM-031 are likely to work in Aβ aggregation reduction and neuroprotection, providing insight into the possible application in AD treatment.

    Keywords: Alzheimer’s disease, amyloid β, chalcone-coumarin hybrid, anti-oxidation, anti-apoptosis.

    目錄 目錄 I 中文摘要 IV Abstract VI 圖表次 VIII 壹、 緒論 1 一、 阿茲海默氏症(Alzheimer's disease) 1 二、 Amyloid-β (Aβ)胜肽 2 三、 HSPB1、Aβ聚集與阿茲海默氏症 4 四、 乙醯膽鹼、乙醯膽鹼脂酶及乙醯膽鹼脂酶抑制劑 5 五、 NRF2、抗氧化壓力與阿茲海默氏症 6 六、 CREB、神經生長與阿茲海默氏症 7 七、 甘草查爾酮A (Licochalcone A)、香豆素(Coumarin)及待測化合物 10 八、 藥物篩檢研究 12 貳、 研究目的 14 參、 研究材料與方法 15 一、 DPPH自由基清除能力檢測 15 二、 Thioflavin T 螢光亮度檢測 15 三、 細胞培養與繼代 16 四、 化合物毒性測試 16 五、 Aβ-GFP細胞模式螢光亮度照相 17 六、 Aβ-GFP細胞模式篩檢 17 七、 Aβ-GFP細胞模式毒性測試 18 八、 Aβ-GFP 細胞模式Aβ-GFP RNA表現量檢測 18 九、 活性氧化物檢測 19 十、 凋亡蛋白酶-3活性檢測 20 十一、 神經突生長觀測 21 十二、 乙醯膽鹼脂酶活性測試 22 十三、 西方轉漬法 23 十四、 統計分析 25 肆、 結果 26 一、 DPPH自由基清除能力分析 26 二、 Thioflavin T 螢光分析 26 三、 待測化合物細胞毒性分析 27 四、 正控制組薑黃素的Aβ-GFP 293細胞分析 27 五、 待測化合物的Aβ-GFP 293細胞篩檢分析 28 六、 待測化合物Aβ-GFP 293細胞毒性分析 29 七、 化合物處理Aβ-GFP293細胞模式的Aβ-GFP RNA表現量 分析 30 八、 活性氧化物分析 31 九、 凋亡蛋白酶-3活性分析 31 十、 神經突生長分析 32 十一、 凋亡蛋白酶-3蛋白表現量分析 33 十二、 乙醯膽鹼脂酶活性分析 34 十三、 NRF2與下游抗氧化壓力蛋白表現量分析 35 十四、 CREB與下游神經生長相關蛋白表現量分析 37 伍、 討論 40 陸、 參考文獻 50 柒、 附錄圖表 72

    王立娟, 王鑒, 王焱鵬, 謝文傑. (2008) 酚類抗氧劑的結構特徵與發展方向。四川化工。8:16-19.
    孟慶華, 于曉霞, 張海鳳, 張紹良. (2012) 天然黃酮類化合物清除自由基機理及其應用進展。雲南民族大學學報:自然科學版。21:79-83.
    陳永鈞, 龍曉英, 潘素靜. (2013) 黃酮類化合物的藥效機制及構效關係研究進展。中國實驗方劑學雜誌。19:337-343.
    黃鉦翔. (2012) 以amyloid-β聚集為目標的阿茲海默氏症治療策略。國立臺灣師範大學生命科學系碩士論文。
    Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. (1999) Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 274:26071-26078.
    Anand P, Singh B, Singh N. (2012) A review on coumarins as acetylcholinesterase inhibitors for Alzheimer's disease. Bioorg Med Chem. 20:1175-1180.
    Bayer TA, Wirths O. (2008) Review on the APP/PS1KI mouse model: intraneuronal Aβ accumulation triggers axonopathy, neuron loss and working memory impairment. Genes Brain Behav. 7:6-11.
    Barnabé-Heider F, Miller FD. (2003) Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci. 23:5149-5160.
    Bartus RT, Dean RL, Beer B, Lippa AS. (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science. 217:408-414.
    Bendary E, Francis RR, Ali HMG, Sarwat MI, El Hady S. (2013) Antioxidant and structure–activity relationships (SARs) of some phenolic and anilines compounds. Annals Agric Sci. 58:173-181.
    Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 286:1358-1362.
    Bruey J-M, Ducasse C, Bonniaud P, Ravagnan L, Susin SA, Diaz-Latoud C, Gurbuxani S, Arrigo AP, Kroemer G, Solary E, Garrido C. (2000) Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol. 2:645-652.
    Brunelle JK, Letai A. (2009) Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 122:437-441.
    Bullock BP, Habener JF. (1998) Phosphorylation of the cAMP response element binding protein CREB by cAMP-dependent protein kinase A and glycogen synthase kinase-3 alters DNA binding affinity, conformation, and increases net charge. Biochemistry. 37:3795-3809.
    Butterfield DA. (1997) beta-Amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer's disease. Chem Res Toxicol. 10:495-506.
    Butterfield DA, Drake J, Pocernich C, Castegna A. (2001) Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide. Trends Mol Med. 7:548-554.
    Butterfield DA, Reed T, Newman SF, Sultana R. (2007) Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radic Biol Med. 43:658-677.
    Campanari ML, García-Ayllón MS, Blazquez-Llorca L, Luk WK, Tsim K, Sáez-Valero J. (2014) Acetylcholinesterase protein level is preserved in the Alzheimer's brain. J Mol Neurosci. 53:446-453.
    Cerpa W, Dinamarca MC, Inestrosa NC. (2008) Structure-function implications in Alzheimer's disease: effect of Aβ oligomers at central synapses. Curr Alzheimer Res. 5:233-243.
    Chang KH, Chiu YJ, Chen SL, Huang CH, Lin CH, Lin TH, Lee CM, Ramesh C, Wu CH, Huang CC, Fung HC, Chen YC, Lin JY, Yao CF, Huang HJ, Lee-Chen GJ, Lee MC, Hsieh-Li HM. (2016) The potential of synthetic indolylquinoline derivatives for Aβ aggregation reduction by chemical chaperone activity. Neuropharmacology. 101:309-319.
    Chang KH, Lin CH, Chen HC, Huang HY, Chen SL, Lin TH, Ramesh C, Huang CC, Fung HC, Wu YR, Huang HJ, Lee-Chen GJ, Hsieh-Li HM, Yao CF. (2017) The potential of indole/indolylquinoline compounds in tau misfolding reduction by enhancement of HSPB1. CNS Neurosci Ther. 23:45-56.
    Chen CM, Weng YT, Chen WL, Lin TH, Chao CY, Lin CH, Chen IC, Lee LC, Lin HY, Wu YR, Chen YC, Chang KH, Tang HY, Cheng ML, Lee-Chen GJ, Lin JY. (2014) Aqueous extract of Glycyrrhiza inflata inhibits aggregation by upregulating PPARGC1A and NFE2L2-ARE pathways in cell models of spinocerebellar ataxia 3. Free Radic Biol Med. 71:339-350.
    Chen DF, Schneider GE, Martinou JC, Tonegawa S. (1997) Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature. 385:434-439.
    Christensen DZ, Bayer TA, Wirths O. (2010) Intracellular Aβ triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging. 31:1153-1163.
    Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH. (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 365:855-859.
    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 261:921-923.
    Csermely P. (2001) Chaperone overload is a possible contributor to ‘civilization diseases’. Trends Genet. 17:701-704.
    Cullen WK, Suh YH, Anwyl R, Rowan MJ. (1997) Block of LTP in rat hippocampus in vivo by β-amyloid precursor protein fragments. Neuroreport. 8:3213-3217.
    Davies P, Maloney AJ. (1976) Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 2:1403.
    Dhakshinamoorthy S, Jaiswal AK. (2001) Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene. 20:3906-3917.
    Du H, Guo L, Wu X, Sosunov AA, McKhann GM, Chen JX, Yan SS. (2014) Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim Biophys Acta. 1842:2517-2527.
    Enz A., Floersheim P. (1997) Cholinesterase inhibitors: an overview of their mechanisms of action. In: Becker RGE, ed. Alzheimer's Disease: From Molecular Biology to Therapy. Boston, Mass: Birkhauser 211-215.
    Farinola N, Piller N. (2005) Pharmacogenomics: Its role in re-establishing coumarin as treatment for lymphedema. Lymphat Res Biol. 3:81-86.
    Favrin G, Irbäck A, Mohanty S. (2004) Oligomerization of amyloid Aβ16-22 peptides using hydrogen bonds and hydrophobicity forces. Biophys J. 87:3657-3664.
    Funato H, Yoshimura M, Kusui K, Tamaoka A, Ishikawa K, Ohkoshi N, Namekata K, Okeda R, Ihara Y. (1998) Quantitation of amyloid β-protein (Aβ) in the cortex during aging and in Alzheimer's disease. Am J Pathol. 152:1633-1640.
    Ganea E. (2001) Chaperone-like activity of alpha-crystallin and other small heat shock proteins. Curr Protein Pept Sci. 2:205-225.
    García-Ayllón MS, Riba-Llena I, Serra-Basante C, Alom J, Boopathy R, Sáez-Valero J. (2010) Altered levels of acetylcholinesterase in Alzheimer plasma. PLoS One. 5:e8701.
    Garrido C, Bruey JM, Fromentin A, Hammann A, Arrigo AP, Solary E. (1999) HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J. 13:2061-2070.
    Garzon DJ, Fahnestock M. (2007) Oligomeric amyloid decreases basal levels of brain-derived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells. J Neurosci. 27:2628-2635.
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 349:704-706.
    Gonzalez GA, Montminy MR. (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 59:675-680.
    Gorski JA, Zeiler SR, Tamowski S, Jones KR. (2003) Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J Neurosci. 23:6856-6865.
    Grimes CA, Jope RS (2001) CREB DNA binding activity is inhibited by glycogen synthase kinase-3β and facilitated by lithium. J Neurochem. 78:1219-1232.
    Hardy J, Selkoe DJ. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297:353-356.
    Hardy J. (2009) The amyloid hypothesis for Alzheimer's disease: a critical reappraisal. J Neurochem. 110:1129-1134.
    Hilton M, Middleton G, Davies AM. (1997) Bcl-2 influences axonal growth rate in embryonic sensory neurons. Curr Biol. 7:798-800.
    Inestrosa NC, Alvarez A, Pérez CA, Moreno RD, Vicente M, Linker C, Casanueva OI, Soto C, Garrido J. (1996) Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron. 16:881-891.
    Inestrosa NC, Dinamarca MC, Alvarez A. (2008) Amyloid-cholinesterase interactions. Implications for Alzheimer’s disease. FEBS J. 275:625-632.
    Islam O, Loo TX, Heese K. (2009) Brain-derived neurotrophic factor (BDNF) has proliferative effects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways. Curr Neurovasc Res. 6:42-53.
    Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13:76-86.
    Iwaki T, Wisniewski T, Iwaki A, Corbin E, Tomokane N, Tateishi J, Goldman JE. (1992) Accumulation of αB-crystallin in central nervous system glia and neurons in pathologic conditions. Am J Pathol. 140:345-356.
    Jakob U, Gaestel M, Engel K, Buchner J. (1993) Small heat shock proteins are molecular chaperones. J Biol Chem. 268:1517-1520.
    Joshi G, Johnson JA. (2012) The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent Pat CNS Drug Discov. 7:218-229.
    Kanninen K, Malm TM, Jyrkkänen HK, Goldsteins G, Keksa-Goldsteine V, Tanila H, Yamamoto M, Ylä-Herttuala S, Levonen AL, Koistinaho J. (2008) Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci. 39:302-313.
    Kärkkäinen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A, Lehtonen S, Naumenko N, Tavi P, Levonen AL, Yamamoto M, Malm T, Magga J, Kanninen KM, Koistinaho J. (2014) Nrf2 regulates neurogenesis and protects neural progenitor cells against Aβ toxicity. Stem Cells. 32:1904-1916.
    Khodagholi F, Ashabi G. (2013) Dietary supplementation with Salvia sahendica attenuates memory deficits, modulates CREB and its down-stream molecules and decreases apoptosis in amyloid beta-injected rats. Behav Brain Res. 241:62-69.
    Khurana R, Coleman C, Ionescu-Zanetti C, Carter SA, Krishna V, Grover RK, Roy R, Singh S. (2005) Mechanism of thioflavin T binding to amyloid fibrils. J Struct Biol. 151:229-238.
    Kim W, Kim Y, Min J, Kim DJ, Chang YT, Hecht MH. (2006) A high throughput screen for compounds that inhibit aggregation of the Alzheimer's peptide. ACS Chem Biol. 1:461-469.
    King M, Nafar F, Clarke J, Mearow K. (2009) The small heat shock protein Hsp27 protects cortical neurons against the toxic effects of β-amyloid peptide. J Neurosci Res. 87:3161-3175.
    Kontogiorgis CA, Xu Y, Hadjipavlou-Litina D, Luo Y. (2007) Coumarin derivatives protection against ROS production in cellular models of Abeta toxicities. Free Radic Res. 41:1168-1180.
    Kostova I, Bhatia S, Grigorov P, Balkansky S, Parmar VS, Prasad AK, Saso L. (2011) Coumarin as antioxidants. Curr Med Chem. 18:3929-3951.
    Kosugi T, Satoh K, Yamamoto A, Hoshi K, Aoki Y, Takagaki H, Ichihara K. (2000) Radical scavenging properties of novel benzopyran derivatives, TA248 and TA276, and effects of the compounds on ischemic/reperfused myocardium in dogs. J Pharm Sci. 89:1114-1122.
    Kudva YC, Hiddinga HJ, Butler PC, Mueske CS, Eberhardt NL. (1997) Small heat shock proteins inhibit in vitro Aβ1-42 amyloidogenesis. FEBS Lett. 416:117-121.
    Landry J, Huot J. (1995) Modulation of actin dynamics during stress and physiological stimulation by a signaling pathway involving p38 MAP kinase and heat-shock protein 27. Biochem Cell Biol. 73:703-707.
    Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, Yamaguchi H, Ruiz A, Martinez A, Madrigal L, Hincapie L, Arango JC, Anthony DC, Koo EH, Goate AM, Selkoe DJ, Arango JC. (1996) The E280A presenilin 1 Alzheimer mutation produces increased Aβ 42 deposition and severe cerebellar pathology. Nat Med. 2:1146-1150.
    Li M, Dai FR, Du XP, Yang QD, Zhang X, Chen Y. (2012) Infusion of BDNF into the nucleus accumbens of aged rats improves cognition and structural synaptic plasticity through PI3K-ILK-Akt signaling. Behav Brain Res. 231:146-153.
    Liang JH, Du J, Xu LD, Jiang T, Hao S, Bi J. (2009) Catalpol protects primary cultured cortical neurons induced by Aβ1–42 through a mitochondrial-dependent caspase pathway. Neurochem Int. 55:741-746.
    Lowe TL, Strzelec A, Kiessling LL, Murphy RM. (2001) Structure-function relationships for inhibitors of β-amyloid toxicity containing the recognition sequence KLVFF. Biochemistry. 40:7882-7889.
    Lu B. (2003) BDNF and activity-dependent synaptic modulation. Learn. 10:86-98.
    Ma QL, Harris-White ME, Ubeda OJ, Simmons M, Beech W, Lim GP, Teter B, Frautschy SA, Cole GM. (2007) Evidence of Aβ- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models. J Neurochem. 103:1594-1607.
    Mathew A, Fukuda T, Nagaoka Y, Hasumura T, Morimoto H, Yoshida Y, Maekawa T, Venugopal K, Kumar DS. (2012) Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 peptide for potential use in Alzheimer's disease. PLoS One 7:e32616.
    Matos MJ, Vazquez-Rodriguez S, Santana L, Uriarte E, Fuentes-Edfuf C, Santos Y, Muñoz-Crego A. (2012) Looking for new targets: simple coumarins as antibacterial agents. Med Chem. 8:1140-1145.
    Meller R, Minami M, Cameron JA, Impey S, Chen D, Lan JQ, Henshall DC, Simon RP. (2005) CREB-mediated Bcl-2 protein expression after ischemic preconditioning. J Cereb Blood Flow Metab. 25:234-246.
    Meng Y, Xu H, Wang R, Ji Z, Yu S, Zhou J, Sheng S. (2002) Impairment of signal transduction pathway on neuronal survival in brains of Alzheimer's disease. Zhonghua Bing Li Xue Za Zhi. 31:502-505.
    Merry DE, Veis DJ, Hickey WF, Korsmeyer SJ. (1994) bcl-2 protein expression is widespread in the developing nervous system and retained in the adult PNS. Development. 120:301-311.
    Mesulam MM, Asuncion Morán M. (1987) Cholinesterases within neurofibrillary tangles related to age and Alzheimer's disease. Ann Neurol. 22:223-228.
    Micha M. M. Wilhelmus, Robert M. W. de Waal, Marcel M. Verbeek. (2007) Heat shock proteins and amateur chaperones in amyloid-beta accumulation and clearance in Alzheimer's disease. Mol Neurobiol. 35:203-216.
    Muñoz-Torrero D. (2008) Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer's disease. Curr Med Chem. 15:2433-2455.
    Murray PS, Holmes PV. (2011) An overview of brain-derived neurotrophic factor and implications for excitotoxic vulnerability in the hippocampus. Int J Pept. 2011:654085.
    Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA. (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci. 18:3659-3668.
    Nemes Z, Devreese B, Steinert PM, Van Beeumen J, Fesus L. (2004) Cross-linking of ubiquitin, HSP27, parkin, and α-synuclein by γ-glutamyl-epsilon-lysine bonds in Alzheimer’s neurofibrillary tangles. FASEB J. 18:1135-1137.
    Nolte H, Pedersen L, Mouridsen HT. (1987) Combined treatment of advanced malignant melanoma with coumarin and cimetidine. Anticancer Res. 7:449-450.
    Nunan J, Small DH. (2000) Regulation of APP cleavage by α-, β- and γ-secretases. FEBS Lett. 483:6-10.
    Ojha J, Masilamoni G, Dunlap D, Udoff RA, Cashikar AG. (2011) Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism. Mol Cell Biol. 31:3146-3157.
    Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL, Lu B. (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 306:487-491.
    Parihar MS, Hemnani T. (2004) Alzheimer's disease pathogenesis and therapeutic interventions. J Clin Neurosci. 11:456-467.
    Pérez-Cruz F, Vazquez-Rodriguez S, Matos MJ, Herrera-Morales A, Villamena FA, Das A, Gopalakrishnan B, Olea-Azar C, Santana L, Uriarte E. (2013) Synthesis and electrochemical and biological studies of novel coumarin−chalcone hybrid compounds. J Med Chem. 56:6136-6145.
    Perry EK, Perry RH, Blessed G, Tomlinson BE. (1977) Necropsy evidence of central cholinergic deficits in senile dementia. Lancet. 1:189.
    Picone P, Nuzzo D, Caruana L, Scafidi V, Di Carlo M. (2014) Mitochondrial dysfunction: different routes to Alzheimer's disease therapy. Oxid Med Cell Longev. 2014:780179.
    Portt L, Norman G, Clapp C, Greenwood M, Greenwood MT. (2011) Anti-apoptosis and cell survival: a review. Biochim Biophys Acta. 1813:238-259.
    Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE. (2000) Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem. 275:10761-10766.
    Pugazhenthi S, Miller E, Sable C, Young P, Heidenreich KA, Boxer LM, Reusch JE-B. (1999) Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response element binding protein. J Biol Chem. 274:27529-27535.
    Pugazhenthi S, Wang M, Pham S, Sze CI, Eckman CB. (2011) Downregulation of CREB expression in Alzheimer’s brain and in Aβ-treated rat hippocampal neurons. Mol Neurodegener. 6:60.
    Querfurth HW, LaFerla FM. (2010) Alzheimer's disease. N Engl J Med. 362:329-344.
    Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL. (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol. 66:75-85.
    Rane MJ, Pan Y, Singh S, Powell DW, Cummins T, Wu R, Chen Q, McLeish KR, Klein JB (2003) Heat shock protein 27 controls neutrophil survival by regulating PKB/Akt activation. J Biol Chem. 278:27828-27835.
    Rangachari V, Moore BD, Reed DK, Sonoda LK, Bridges AW, Conboy E, Hartigan D, Rosenberry TL. (2007) Amyloid-β(1-42) rapidly forms protofibrils and oligomers by distinct pathways in low concentrations of sodium dodecylsulfate. Biochemistry: 46:12451-12462.
    Renkawek K, Bosman G J, de Jong WW (1994) Expression of small heat-shock protein hsp 27 in reactive gliosis in Alzheimer disease and other types of dementia. Acta Neuropathol. 87: 511-51910.
    Reyes AE, Perez DR, Alvarez A, Garrido J, Gentry MK, Doctor BP, Inestrosa NC. (1997) A monoclonal antibody against acetylcholinesterase inhibits the formation of amyloid fibrils induced by the enzyme. Biochem Biophys Res Commun. 232:652-655.
    Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD. (1999) Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science. 286:2358-2361.
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, Mar L, Sorbi S, Nacmias B, Piacentini S, Amaducci L, Chumakov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM, St George-Hyslop PH. (1995) Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 376:775-778.
    Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, Ball MJ. (1993) β-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci USA. 90:10836-10840.
    Rossor MN, Fox NC, Freeborough PA, Harvey RJ. (1996) Clinical features of sporadic and familial Alzheimer's disease. Neurodegeneration. 5:393-397.
    Saeed SM, Fine G. (1967) Thioflavin-T for amyloid detection. Am J Clin Pathol. 47:588-593.
    Saini HS, Gorse KM, Boxer LM, Sato-Bigbee C. (2004) Neurotrophin-3 and a CREB-mediated signaling pathway regulate Bcl-2 expression in oligodendrocyte progenitor cells. J Neurochem. 89:951-961.
    Scherzer-Attali R, Pellarin R, Convertino M, Frydman-Marom A, Egoz-Matia N, Peled S, Levy-Sakin M, Shalev DE, Caflisch A, Gazit E, Segal D. (2010) Complete phenotypic recovery of an Alzheimer's disease model by a quinone-tryptophan hybrid aggregation inhibitor. PLoS One. 5:e11101.
    Schneider LS. (2000) A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer's disease. Dialogues Clin Neurosci. 2:111-128.
    Scott G. (1963) Chem and Ind (London) 271.
    Seidah NG, Benjannet S, Pareek S, Chrétien M, Murphy RA. (1996) Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett. 379:247-250.
    Selkoe DJ. (1989) Amyloid β protein precursor and the pathogenesis of Alzheimer's disease. Cell. 58:611-612.
    Serra S, Chicca A, Delogu G, Vazquez-Rodriguez S, Santana L, Uriarte E, Casu L, Gertsch J. (2012) Synthesis and cytotoxic activity of non-naturally substituted 4-oxycoumarin derivatives. Bioorg Med Chem Lett. 22:5791-5794.
    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 375:754-760.
    Shi YQ, Huang TW, Chen LM, Pan XD, Zhang J, Zhu YG, Chen XC. (2010) Ginsenoside Rg1 attenuates amyloid-β content, regulates PKA/CREB activity, and improves cognitive performance in SAMP8 mice. J Alzheimers Dis. 19:977-989.
    Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A. (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron. 20:727-740.
    Shimura H, Miura-Shimura Y, Kosik KS. (2004) Binding of tau to heat shock protein 27 leads to decreased concentration of hyperphosphorylated tau and enhanced cell survival. J Biol Chem. 279:17957-17962.
    Storey E, Cappai R. (1999) The amyloid precursor protein of Alzheimer's disease and the Aβ peptide. Neuropathol Appl Neurobiol. 25:81-97.
    Sunde M, Serpell LC, Bartlam M, Fraser PE, Pepys MB, Blake CC. (1997) Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J Mol Biol. 273:729-739.
    Tabner BJ, Turnbull S, El-Agnaf OM, Allsop D. (2002) Formation of hydrogen peroxide and hydroxyl radicals from Aβ and α-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. Free Radic Biol Med. 32:1076-1083.
    Tabuchi A, Sakaya H, Kisukeda T, Fushiki H, Tsuda M. (2002) Involvement of an upstream stimulatory factor as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem. 277:35920-35931.
    Tada-Oikawa S, Oikawa S, Kawanishi S. (1998) Role of ultraviolet A-induced oxidative DNA damage in apoptosis via loss of mitochondrial membrane potential and caspase-3 activation. Biochem Biophys Res Commun. 247:693-696.
    Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 20:709-726.
    Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y. (2007) EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J. 21:2400-2408.
    Tian X, Zhang L, Wang J, Dai J, Shen S, Yang L, Huang P. (2013) The protective effect of hyperbaric oxygen and Ginkgo biloba extract on Aβ25–35-induced oxidative stress and neuronal apoptosis in rats. Behav Brain Res. 242:1-8.
    Tóth ME, Szegedi V, Varga E, Juhász G, Horváth J, Borbély E, Csibrány B, Alföldi R, Lénárt N, Penke B, Sántha M. (2013) Overexpression of Hsp27 ameliorates symptoms of Alzheimer’s disease in APP/PS1 mice. Cell Stress Chaperones. 18:759-771.
    Trebbastoni A, Pichiorri F, D'Antonio F, Campanelli A, Onesti E, Ceccanti M, de Lena C, Inghilleri M. (2016) Altered cortical synaptic plasticity in response to 5-Hz repetitive transcranial magnetic stimulation as a new electrophysiological finding in amnestic mild cognitive impairment converting to Alzheimer's disease: Results from a 4-year prospective cohort study. Front Aging Neurosci. 7:253.
    Tully T, Bourtchouladze R, Scott R, Tallman J. (2003) Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov. 2:267-277.
    Ulrich J, Meier-Ruge W, Probst A, Meier E, Ipsen S. (1990) Senile plaques: staining for acetylcholinesterase and A4 protein: a comparative study in the hippocampus and entorhinal cortex. Acta Neuropathol. 80:624-628.
    Van Montfort R, Slingsby C, Vierling E. (2001) Structure and function of the small heat shock protein/alpha-crystallin family of molecular chaperones. Adv Protein Chem. 59:105-156.
    Van Muiswinkel FL, Kuiperij HB. (2005) The Nrf2-ARE Signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders. Curr Drug Targets CNS Neurol Disord. 4:267-281.
    Vitolo OV, Sant’Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. (2002) Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci USA. 99:13217-13221.
    Waldo GS, Standish BM, Berendzen J, Terwilliger TC. (1999) Rapid protein-folding assay using green fluorescent protein. Nat Biotechnol. 17:691-695.
    Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. (2002) Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 416:535-539.
    Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R. (2004) Block of long-term potentiation by naturally secreted and synthetic amyloid β-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci. 24:3370-3378.
    Wang YJ, Thomas P, Zhong JH, Bi FF, Kosaraju S, Pollard A, Fenech M, Zhou XF. (2009) Consumption of grape seed extract prevents amyloid-β deposition and attenuates inflammation in brain of an Alzheimer's disease mouse. Neurotox Res. 15:3-14.
    Wang Z, Yang L, Zheng H. (2012) Role of APP and Aβ in synaptic physiology. Curr Alzheimer Res. 9:217-226.
    Wei H, Ruan J, Zhang X. (2016) Coumarin-chalcone hybrids: promising agents with diverse pharmacological properties. RSC Advances. 6:10846-10860.
    Wilhelmus MM, Otte-Holler I, Wesseling P, de Waal RM, Boelens WC, Verbeek MM. (2006a) Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains. Neuropathol Appl Neurobiol. 32:119-130.
    Wilhelmus MM, Boelens WC, Otte-Höller I, Kamps B, de Waal RM, Verbeek MM. (2006b). Small heat shock proteins inhibit amyloid-β protein aggregation and cerebrovascular amyloid-β protein toxicity. Brain Res. 1089:67-78.
    Wilson BE, Mochon E, Boxer LM. (1996) Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. Mol Cell Biol. 16:5546-5556.
    Wu C, Wang Z, Lei H, Zhang W, Duan Y. (2007) Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. J Am Chem Soc. 129:1225-1232.
    Yakel JL. (2013) Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease. Pflugers Arch. 465:441-450.
    Yan X, Liu J, Ye Z, Huang J, He, Xiao W, Hu X, Luo Z. (2016) CaMKII-mediated CREB phosphorylation is involved in Ca2+-induced BDNF mRNA transcription and neurite outgrowth promoted by electrical stimulation. PLoS One. 11:e0162784.
    Yang H, Magilnick N, Lee C, Kalmaz D, Ou X, Chan JY, Lu SC. (2005) Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1. Mol Cell Biol. 25:5933-5946.
    Yang Y, Jiang S, Yan J, Li Y, Xin Z, Lin Y, Qu Y. (2015) An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders. Cytokine Growth Factor Rev. 26:47-57.
    Ye J, Meng X, Yan C, Wang C. (2010) Effect of purple sweet potato anthocyanins on β-amyloid-mediated PC-12 cells death by inhibition of oxidative stress. Neurochem Res. 35:357-365.
    Ying SW, Futter M, Rosenblum K, Webber M, Hunt SP, Bliss TV, Bramham CR. (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci. 22:1532-1540.
    Zanassi P, Paolillo M, Feliciello A, Avvedimento EV, Gallo V, Schinelli S. (2001) cAMP-dependent protein kinase induces cAMP-response element-binding protein phosphorylation via an intracellular calcium release/ERK-dependent pathway in striatal neurons. J Biol Chem. 276:11487-11495.
    Zhang YW, Thompson R, Zhang H, Xu H. (2011) APP processing in Alzheimer's disease. Mol Brain. 4:3.
    Zhao L, Feng Y, Hu H, Shi A, Zhang L, Wan M. (2016) Low-intensity pulsed ultrasound enhances nerve growth factor-induced neurite outgrowth through mechanotransduction-mediated ERK1/2-CREB- Trx-1 signaling. Ultrasound Med Biol. 42:2914-2925.
    Zhao T, Zeng Y, Kermode AR. (2012) A plant cell-based system that predicts aβ42 misfolding: potential as a drug discovery tool for Alzheimer's disease. Mol Genet Metab. 107:571-579.
    Zhong SZ, Ma SP, Hong ZY. (2013) Peoniflorin activates Nrf2/ARE pathway to alleviate the Abeta(1-42)-induced hippocampal neuron injury in rats. Yao Xue Xue Bao. 48:1353-1357.

    下載圖示
    QR CODE