國立臺灣師範大學博碩士論文全文系統

簡易檢索 / 詳目顯示

回結果列表

研究生：	黃頂翔 Huang, Ding-Siang
論文名稱：	脊髓小腦萎縮症第十七型及阿茲海默氏症神經保護中草藥的研究 Neuroprotective Chinese herbal medicines against polyQ-mediated spinocerebellar ataxia type 17 and Alzheimer’s disease
指導教授：	吳忠信 Wu, Chung-Hsin 林榮耀 Lin, Jung-Yaw
學位類別：	博士 Doctor
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：	英文
論文頁數：	78
中文關鍵詞：	中草藥、脊髓小腦萎縮症第十七型、興奮性毒性、多麩醯胺疾病、細胞凋亡、阿茲海默氏症、三重阿茲海默氏症基因轉殖小鼠、神經保護
英文關鍵詞：	Chinese herbal medicine, spinocerebellar ataxia type 17, polyQ diseases, excitotoxicity, Alzheimer’s disease, apoptosis, triple transgenic AD mice, neuroprotection
DOI URL：	https://doi.org/10.6345/NTNU202202215
論文種類：	學術論文
相關次數：	點閱：189 下載：7
分享至:	分享至facebook 分享至twitter

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

多麩醯胺（PolyQ）介導的神經退行性疾病是由各種蛋白質的多麩醯胺擴增引起的。而脊髓小腦萎縮症第十七型（SCA 17）是由TATA盒結合蛋白（TATA box-binding protein, TBP）基因中CAG / CAA重複擴增引起的多麩醯胺疾病。銀杏葉提取物EGb 761含有黃酮和萜類化合物，可用於治療神經退化性疾病如阿茲海默氏症與帕金森氏病。雖然EGb 761的神經保護作用的功能已經被證實，但是EGb 761對於治療SCA 17是否具有效果則尚不清楚。為解決此一問題，我們利用表達TBP/79Q的SH-SY5Y細胞，以及具有人類突變型TBP基因的SCA17轉基因小鼠進行實驗。我們的研究成果發現利用EGb 761處理TBP/79Q-SH-SY5Y細胞後，細胞內十二烷基硫酸鈉不溶性蛋白質的含量會明顯減少；我們進一步發現，EGb 761處理可以抑制TBP/79Q-SH-SY5Y細胞的興奮性毒性以及鈣離子流入，並且降低經麩醯胺酸鹽處理SH-SY5Y神經母細胞瘤細胞的細胞凋亡標誌物表達。活體實驗中，我們每天利用腹腔內注射EGb 761（100 mg/kg）給予SCA 17轉基因小鼠，實驗結果發現EGb761可以有效緩解SCA 17轉基因小鼠的運動缺陷。由上述研究結果提供證據證實利用SCA 17的細胞與轉基因小鼠模型，EGb 761可以通過抑制神經細胞的興奮性毒性和細胞凋亡來達到治療SCA 17的效果。為此，我們認為EGb 761可能是有效治療SCA 17的潛在治療藥物。除罕見的遺傳性SCA 17外，阿茲海默氏症（AD）是最常見的神經退化性疾病，AD特徵在於受影響腦區域中形成澱粉樣蛋白-β肽的胞外斑塊，以及細胞內微管相關蛋白tau因為過度磷酸化聚集形成的神經原纖維纏結。在本研究中，我們探討X蛋白質對於乙型類澱粉蛋白聚合的影響，我們也發現綠茶內的其中一種茶多酚，Epigallocatechin gallate (EGCG) 能抑制X蛋白質對於乙型類澱粉蛋白的聚合作用，亦能增加細胞存活率。此外經過EGCG處理的三重轉基因AD小鼠（h-APPSwe，h-tauP301L和h-PS1M146V），通過Morris水迷宮、Y迷宮和新穎的對象識別的動物行為測試實驗，發現轉基因AD小鼠的記憶學習均獲得顯著的改善。因此，我們認為EGCG可能透過抑制X蛋白質而有效治療AD的多功能潛在治療藥物。

Spinocerebellar ataxia type 17 (SCA 17) is a polyglutamine disease caused by the expansion of CAG/CAA repeats (> 43 repeats) in the TATA box-binding protein (TBP) gene. The Ginkgo biloba extracts EGb 761 contain flavonoids and terpenoids with a potential use for the treatment of neurodegenerative diseases such as Parkinson's disease, but whether the EGb 761 has therapeutic effects in SCA 17 are still unclear. To investigate our issues, we have generated TBP/79Q-expressing SH-SY5Y cells, and SCA 17 transgenic mice with the mutant hTBP gene. In vitro experiment, we observed that the EGb 761 treatment decreased the amount of sodium dodecyl sulfate-insoluble proteins in the TBP/79Q-expressing SH-SY5Y cells. We further found that the EGb 761 treatment could inhibit excitotoxicity and calcium influx, and reduce the expression of apoptotic markers in glutamate-treated SH-SY5Y neuroblastoma cells. In vivo experiment, we observed that the EGb 761 treatment (100 mg/kg intraperitoneally injection every other day) could relieve the motor deficiencies of the SCA 17 transgenic mice. Our findings provide evidence that the EGb 761 treatment can remedy for SCA 17 via suppressing excitotoxicity and apoptosis in SCA 17 cells and animal models. Therefore, it indicates that EGb 761 could be a potential therapeutic agent for treating SCA 17.
Apart from rare inherited SCA 17, Alzheimer’s disease (AD) is the most common neurodegenerative disease and characterized by the formation extracellular plaques of the amyloid-β peptide and intracellular neurofibrillary tangles of hyperphosphorylated aggregates of microtubule-associated protein tau in affected brain regions. We examined the effects of epigallocatechin gallate (EGCG) on Aβ oliogmerization induced by protein X, and found that EGCG attenuated amyloidogenic pathway promoted by protein X. EGCG also increased the cell viability after Aβ treatment in SH-SY5Y/protein X cells. Furthermore, EGCG treatment improved the performance of triple transgenic AD mice (h-APPswe, h-TauP301L, and h-PS1M146V) in the Morris water maze, Y maze and novel object recognition test. Collectively, these results suggest that EGCG could be a promising multifunctional drug candidate for AD by inhibiting protein X.

CONTENTS
CONTENTS    I
LIST OF FIGURES    V
中文摘要    VII
ABSTRACT    IX

CHAPTER 1. GENERAL INTRODUCTION    1
1.1 Neurodegeneration    2
1.2 Chinese herbal medicines    2
1.3 Research aims    4

CHAPTER 2. PROTECTIVE EFFECTS OF EGb 761 AGAINST SPINOCEREBELLAR ATAXIA TYPE 17 BY INHIBITOION OF EXCITOXICITY PATHWAY    6
2.1 Introduction    7
2.2 Materials and Methods    9
2.2.1 Materials    9
2.2.2 Cell culture    10
2.2.3 Cell viability assay    10
2.2.4 Measurement of calcium influx    11
2.2.5 Western blot analysis    11
2.2.6 Dot blot assay    12
2.2.7 Animals    13
2.2.8 Rotarod performance    14
2.2.9 Immunohistochemistry (IHC)    15
2.2.10 Statistical analysis    16
2.3 Results    17
2.3.1 Effects of EGb 761 on glutamate-induced cytotoxicity    17
2.3.2 Inhibition effects of EGb 761 on calcium influx induced by glutamate    17
2.3.3 Inhibition effects of EGb 761 on glutamate-mediated cell apoptosis    18
2.3.4 EGb 761 suppresses TBP/79Q aggregation and apoptosis in the TBP/79Q-EGFP cells    19
2.3.5 EGb 761 ameliorates the motor function of the SCA 17 transgenic mice    20
2.4 Discussion    33
2.5 References    36

CHAPTER 3. PROTECTIVE EFFECTS OF EGCG AGAINST Αβ42 OLIGOMERIZATION INDUCED BY PROTEIN X    47
3.1 Introduction    48
3.2 Materials and Methods    50
3.2.1 Materials    50
3.2.2 Cell culture, construction of expression plasmids and transfection    50
3.2.3 Target identification using drug affinity responsive target stability (DARTS)    51
3.2.4 Thioflavin T assay    52
3.2.5 Pull down assay and western blot analysis    52
3.2.6 Dot-blot assay    53
3.2.7 Animals    53
3.2.8 Water maze test    54
3.2.9 Y maze task    54
3.2.10 Novel object recognition experiment    55
3.2.11 Statistical analysis    55
3.3 Results    56
3.3.1 Protein X interacts with Aβ42 and increases Aβ42 oligomerization    56
3.3.2 EGCG inhabits Protein X-induced Aβ42 oligomerization and fibrillization    56
3.3.3 Effects of EGCG on Aβ42 cytotoxicity that enhanced by protein X    57
3.3.4 EGCG ameliorates the memory deficits of 3xTg-AD mice    58
3.4 Discussion    68
3.5 References    70

APPENDIX    77
Table 1 Pathological features of neurodegenerative diseases    78

 
LIST OF FIGURES
Figure 1 EGb 761 increased cell viability after glutamate-induced excitotoxicity in SH-SY5Y cells    23
Figure 2 EGb 761 increased calcium influx after glutamate-induced excitotoxicity in SH-SY5Y cells    24
Figure 3 Treatment with EGb 761 downregulated apoptosis markers induced by glutamate    25
Figure 4 EGb 761 reversed mitochondrial dysfunction after glutamate induced excitotoxicity in SH-SY5Y cells    26
Figure 5 Suppression of protein aggregation by EGb 761 in the TBP/79Q-EGFP cells    27
Figure 6 Inhibitory effects of EGb 761 on apoptosis in TBP/79Q-EGFP cells    28
Figure 7 EGb 761 suppressed the TBP aggregation in the SCA 17 transgenic mice    29
Figure 8 Protective effects of EGb 761 in the SCA 17 transgenic mice    30
Figure 9 A schematic representation of protective effects of EGb 761 on SCA 17    32
Figure 10 Interaction between Aβ42 and protein X    60
Figure 11 EGCG Suppressed the A11 positive oligomers induced by protein X    61
Figure 12 Effects of EGCG on protein X-induced Aβ42 fibrillization    62
Figure 13 Effects of EGCG on Aβ42 cytotoxicity and Aβ42 oligomerization induced by protein X    63
Figure 14 EGCG alleviated the memory impairments in 3xTg AD mice    65
Figure 15 A schematic representation of effects of EGCG on amyloidogenic pathway induced by protein X    67
                                

Ch. 2
1. Ross, C. A., and Poirier, M. A. (2004) Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl, S10-17
2. Soto, C. (2003) Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4, 49-60
3. Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., Regan, C. M., Walsh, D. M., Sabatini, B. L., and Selkoe, D. J. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14, 837-842
4. Selkoe, D. J. (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192, 106-113
5. Townsend, M., Shankar, G. M., Mehta, T., Walsh, D. M., and Selkoe, D. J. (2006) Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol 572, 477-492
6. Stefani, M., and Dobson, C. M. (2003) Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med (Berl) 81, 678-699
7. Zhang, H., Lai, Q., Li, Y., Liu, Y., and Yang, M. (2017) Learning and memory improvement and neuroprotection of Gardenia jasminoides (Fructus gardenia) extract on ischemic brain injury rats. J Ethnopharmacol 196, 225-235
8. Gu, Y., Chen, J., and Shen, J. (2014) Herbal medicines for ischemic stroke: combating inflammation as therapeutic targets. J Neuroimmune Pharmacol 9, 313-339
9. Chen, L. W., Wang, Y. Q., Wei, L. C., Shi, M., and Chan, Y. S. (2007) Chinese herbs and herbal extracts for neuroprotection of dopaminergic neurons and potential therapeutic treatment of Parkinsons disease. CNS Neurol Disord Drug Targets 6, 273-281
10. Chandrasekaran, K., Mehrabian, Z., Spinnewyn, B., Drieu, K., and Fiskum, G. (2001) Neuroprotective effects of bilobalide, a component of the Ginkgo biloba extract (EGb 761), in gerbil global brain ischemia. Brain Res 922, 282-292
11. Oyama, Y., Chikahisa, L., Ueha, T., Kanemaru, K., and Noda, K. (1996) Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. Brain Res 712, 349-352
12. Bastianetto, S., Ramassamy, C., Doré, S., Christen, Y., Poirier, J., and Quirion, R. (2000) The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci 12, 1882-1890
13. Diamond, B. J., Shiflett, S. C., Feiwel, N., Matheis, R. J., Noskin, O., Richards, J. A., and Schoenberger, N. E. (2000) Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 81, 668-678
14. Ramassamy, C. (2006) Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol 545, 51-64
15. Siddiqui, I. A., Adhami, V. M., Bharali, D. J., Hafeez, B. B., Asim, M., Khwaja, S. I., Ahmad, N., Cui, H., Mousa, S. A., and Mukhtar, H. (2009) Introducing nanochemoprevention as a novel approach for cancer control: proof of principle with green tea polyphenol epigallocatechin-3-gallate. Cancer Res 69, 1712-1716
16. Na, H. K., and Surh, Y. J. (2008) Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food Chem Toxicol 46, 1271-1278
17. Bose, M., Lambert, J. D., Ju, J., Reuhl, K. R., Shapses, S. A., and Yang, C. S. (2008) The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr 138, 1677-1683
18. Wolfram, S., Raederstorff, D., Preller, M., Wang, Y., Teixeira, S. R., Riegger, C., and Weber, P. (2006) Epigallocatechin gallate supplementation alleviates diabetes in rodents. J Nutr 136, 2512-2518
19. Bieschke, J., Russ, J., Friedrich, R. P., Ehrnhoefer, D. E., Wobst, H., Neugebauer, K., and Wanker, E. E. (2010) EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A 107, 7710-7715
20. Singh, N. A., Mandal, A. K., and Khan, Z. A. (2016) Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG). Nutr J 15, 60
21. Ehrnhoefer, D. E., Bieschke, J., Boeddrich, A., Herbst, M., Masino, L., Lurz, R., Engemann, S., Pastore, A., and Wanker, E. E. (2008) EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15, 558-566
22. Guo, Y., Zhao, Y., Nan, Y., Wang, X., Chen, Y., and Wang, S. (2017) (-)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer's disease. Neuroreport 28, 590-597
23. Liu, M., Chen, F., Sha, L., Wang, S., Tao, L., Yao, L., He, M., Yao, Z., Liu, H., Zhu, Z., Zhang, Z., Zheng, Z., Sha, X., and Wei, M. (2014) (-)-Epigallocatechin-3-gallate ameliorates learning and memory deficits by adjusting the balance of TrkA/p75NTR signaling in APP/PS1 transgenic mice. Mol Neurobiol 49, 1350-1363
24. Kung, P. J., Tao, Y. C., Hsu, H. C., Chen, W. L., Lin, T. H., Janreddy, D., Yao, C. F., Chang, K. H., Lin, J. Y., Su, M. T., Wu, C. H., Lee-Chen, G. J., and Hsieh-Li, H. M. (2014) Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models. Drug Des Devel Ther 8, 1929-1939
25. Chang, Y. C., Lin, C. Y., Hsu, C. M., Lin, H. C., Chen, Y. H., Lee-Chen, G. J., Su, M. T., Ro, L. S., Chen, C. M., and Hsieh-Li, H. M. (2011) Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17. J Neurochem 118, 288-303
26. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., and LaFerla, F. M. (2003) Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409-421
27. Fujigasaki, H., Martin, J. J., De Deyn, P. P., Camuzat, A., Deffond, D., Stevanin, G., Dermaut, B., Van Broeckhoven, C., Dürr, A., and Brice, A. (2001) CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia. Brain 124, 1939-1947
28. Nakamura, K., Jeong, S., Uchihara, T., Anno, M., Nagashima, K., Nagashima, T., Ikeda, S., Tsuji, S., and Kanazawa, I. (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10, 1441-1448
29. Zühlke, C., Hellenbroich, Y., Dalski, A., Kononowa, N., Hagenah, J., Vieregge, P., Riess, O., Klein, C., and Schwinger, E. (2001) Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia. Eur J Hum Genet 9, 160-164
30. Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tüting, T., Hoffmann, P., Klockgether, T., Evert, B., Wüllner, U., and Brüstle, O. (2011) Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480, 543-546
31. Hübener, J., Weber, J., Richter, C., Honold, L., Weiss, A., Murad, F., Breuer, P., Wüllner, U., Bellstedt, P., Paquet-Durand, F., Takano, J., Saido, T., Riess, O., and Nguyen, H. (2013) Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Hum Mol Genet 22, 508-518
32. Simões, A., Gonçalves, N., Koeppen, A., Déglon, N., Kügler, S., Duarte, C., and Pereira de Almeida, L. (2012) Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. Brain 135, 2428-2439
33. Tang, T.-S., Tu, H., Chan, E., Maximov, A., Wang, Z., Wellington, C., Hayden, M., and Bezprozvanny, I. (2003) Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39, 227-239
34. Tang, T.-S., Slow, E., Lupu, V., Stavrovskaya, I., Sugimori, M., Llinás, R., Kristal, B., Hayden, M., and Bezprozvanny, I. (2005) Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc Natl Acad Sci U S A 102, 2602-2607
35. Wanker, E. E., Scherzinger, E., Heiser, V., Sittler, A., Eickhoff, H., and Lehrach, H. (1999) Membrane filter assay for detection of amyloid-like polyglutamine-containing protein aggregates. Methods Enzymol 309, 375-386
36. Rothman, S. M., and Olney, J. W. (1995) Excitotoxicity and the NMDA receptor--still lethal after eight years. Trends Neurosci 18, 57-58
37. Sun, Z. W., Zhang, L., Zhu, S. J., Chen, W. C., and Mei, B. (2010) Excitotoxicity effects of glutamate on human neuroblastoma SH-SY5Y cells via oxidative damage. Neurosci Bull 26, 8-16
38. Miao, Y., Dong, L.-D. D., Chen, J., Hu, X.-C. C., Yang, X.-L. L., and Wang, Z. (2012) Involvement of calpain/p35-p25/Cdk5/NMDAR signaling pathway in glutamate-induced neurotoxicity in cultured rat retinal neurons. PLoS One 7, e42318
39. Hardwick, J. M., and Soane, L. (2013) Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol 5, 1-22
40. Koch, E., Nöldner, M., and Leuschner, J. (2013) Reproductive and developmental toxicity of the Ginkgo biloba special extract EGb 761® in mice. Phytomedicine 21, 90-97
41. Mdzinarishvili, A., Sumbria, R., Lang, D., and Klein, J. (2012) Ginkgo extract EGb761 confers neuroprotection by reduction of glutamate release in ischemic brain. J Pharm Pharm Sci 15, 94-102
42. Rojas, P., Serrano-García, N., Mares-Sámano, J. J., Medina-Campos, O. N., Pedraza-Chaverri, J., and Ogren, S. O. (2008) EGb761 protects against nigrostriatal dopaminergic neurotoxicity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice: role of oxidative stress. Eur J Neurosci 28, 41-50
43. Barski, J. J., Hartmann, J., Rose, C. R., Hoebeek, F., Mörl, K., Noll-Hussong, M., De Zeeuw, C. I., Konnerth, A., and Meyer, M. (2003) Calbindin in cerebellar Purkinje cells is a critical determinant of the precision of motor coordination. J Neurosci 23, 3469-3477
44. Whitney, E. R., Kemper, T. L., Rosene, D. L., Bauman, M. L., and Blatt, G. J. (2008) Calbindin-D28k is a more reliable marker of human Purkinje cells than standard Nissl stains: a stereological experiment. J Neurosci Methods 168, 42-47
45. D'Orsi, B., Bonner, H., Tuffy, L., Düssmann, H., Woods, I., Courtney, M., Ward, M., and Prehn, J. (2012) Calpains are downstream effectors of bax-dependent excitotoxic apoptosis. J Neurosci 32, 1847-1858
46. Amar, F., Sherman, M. A., Rush, T., Larson, M., Boyle, G., Chang, L., Götz, J., Buisson, A., and Lesné, S. E. (2017) The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal 10, eaal2021
47. Czeredys, M., Maciag, F., Methner, A., and Kuznicki, J. (2017) Tetrahydrocarbazoles decrease elevated SOCE in medium spiny neurons from transgenic YAC128 mice, a model of Huntington's disease. Biochem Biophys Res Commun 483, 1194-1205
48. Goldberg, J., Guzman, J., Estep, C., Ilijic, E., Kondapalli, J., Sanchez-Padilla, J., and Surmeier, D. (2012) Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease. Nat Neurosci 15, 1414-1421
49. Haacke, A., Hartl, F., and Breuer, P. (2007) Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem 282, 18851-18856
50. Marambaud, P., Dreses-Werringloer, U., and Vingtdeux, V. (2009) Calcium signaling in neurodegeneration. Mol Neurodegener 4, 1-15
51. Bruni, A. C., Takahashi-Fujigasaki, J., Maltecca, F., Foncin, J. F., Servadio, A., Casari, G., D'Adamo, P., Maletta, R., Curcio, S. A., De Michele, G., Filla, A., El Hachimi, K. H., and Duyckaerts, C. (2004) Behavioral disorder, dementia, ataxia, and rigidity in a large family with TATA box-binding protein mutation. Arch Neurol 61, 1314-1320
52. Mariotti, C., Alpini, D., Fancellu, R., Soliveri, P., Grisoli, M., Ravaglia, S., Lovati, C., Fetoni, V., Giaccone, G., Castucci, A., Taroni, F., Gellera, C., and Di Donato, S. (2007) Spinocerebellar ataxia type 17 (SCA17): oculomotor phenotype and clinical characterization of 15 Italian patients. J Neurol 254, 1538-1546
53. Park, S.-H., Kukushkin, Y., Gupta, R., Chen, T., Konagai, A., Hipp, M., Hayer-Hartl, M., and Hartl, F. (2013) PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone. Cell 154, 134-145

Ch. 3
1. Selkoe, D. J. (2011) Alzheimer's disease. Cold Spring Harb Perspect Biol 3, a004457
2. Zempel, H., Luedtke, J., Kumar, Y., Biernat, J., Dawson, H., Mandelkow, E., and Mandelkow, E. M. (2013) Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J 32, 2920-2937
3. Cole, S. L., and Vassar, R. (2007) The Alzheimer's disease beta-secretase enzyme, BACE1. Mol Neurodegener 2, 22
4. Vassar, R., Kovacs, D. M., Yan, R., and Wong, P. C. (2009) The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 29, 12787-12794
5. LaFerla, F. M., Green, K. N., and Oddo, S. (2007) Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 8, 499-509
6. Zhao, L. N., Long, H., Mu, Y., and Chew, L. Y. (2012) The toxicity of amyloid β oligomers. Int J Mol Sci 13, 7303-7327
7. Thal, D. R., Walter, J., Saido, T. C., and Fandrich, M. (2015) Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease. Acta Neuropathol 129, 167-182
8. Li, X. H., Deng, Y. Y., Li, F., Shi, J. S., and Gong, Q. H. (2016) Neuroprotective effects of sodium hydrosulfide against beta-amyloid-induced neurotoxicity. Int J Mol Med 38, 1152-1160
9. Galli, C., Piccini, A., Ciotti, M. T., Castellani, L., Calissano, P., Zaccheo, D., and Tabaton, M. (1998) Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis. Proc Natl Acad Sci U S A 95, 1247-1252
10. Li, Y., Zhou, W., Tong, Y., He, G., and Song, W. (2006) Control of APP processing and Abeta generation level by BACE1 enzymatic activity and transcription. FASEB J 20, 285-292
11. Bertram, L., and Tanzi, R. E. (2008) Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9, 768-778
12. Manczak, M., Anekonda, T. S., Henson, E., Park, B. S., Quinn, J., and Reddy, P. H. (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15, 1437-1449
13. Chen, J. X., and Yan, S. S. (2010) Role of mitochondrial amyloid-beta in Alzheimer's disease. J Alzheimers Dis 20 Suppl 2, S569-578
14. Cadonic, C., Sabbir, M. G., and Albensi, B. C. (2016) Mechanisms of mitochondrial dysfunction in Alzheimer's disease. Mol Neurobiol 53, 6078-6090
15. Lunnon, K., Ibrahim, Z., Proitsi, P., Lourdusamy, A., Newhouse, S., Sattlecker, M., Furney, S., Saleem, M., Soininen, H., Kloszewska, I., Mecocci, P., Tsolaki, M., Vellas, B., Coppola, G., Geschwind, D., Simmons, A., Lovestone, S., Dobson, R., and Hodges, A. (2012) Mitochondrial dysfunction and immune activation are detectable in early Alzheimer's disease blood. J Alzheimers Dis 30, 685-710
16. Caspersen, C., Wang, N., Yao, J., Sosunov, A., Chen, X., Lustbader, J. W., Xu, H. W., Stern, D., McKhann, G., and Yan, S. D. (2005) Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J 19, 2040-2041
17. Fu, Q. Q., Wei, L., Sierra, J., Cheng, J. Z., Moreno-Flores, M. T., You, H., and Yu, H. R. (2016) Olfactory ensheathing cell-conditioned medium reverts Aβ25-35-induced oxidative damage in SH-SY5Y cells by modulating the mitochondria-mediated apoptotic pathway. Cell Mol Neurobiol 37, 1043-1054
18. Tan, J. W., and Kim, M. K. (2016) Neuroprotective effects of biochanin A against beta-amyloid-induced neurotoxicity in PC12 cells via a mitochondrial-dependent apoptosis pathway. Molecules 21, E548
19. Kim, H. S., Lee, J. H., Lee, J. P., Kim, E. M., Chang, K. A., Park, C. H., Jeong, S. J., Wittendorp, M. C., Seo, J. H., Choi, S. H., and Suh, Y. H. (2002) Amyloid beta peptide induces cytochrome C release from isolated mitochondria. Neuroreport 13, 1989-1993
20. Rodrigues, C. M., Sola, S., Silva, R., and Brites, D. (2000) Bilirubin and amyloid-beta peptide induce cytochrome c release through mitochondrial membrane permeabilization. Mol Med 6, 936-946
21. Kim, J., Basak, J. M., and Holtzman, D. M. (2009) The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287-303
22. Liu, C. C., Kanekiyo, T., Xu, H., and Bu, G. (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106-118
23. Schultz, K., Nilsson, K., Nielsen, J. E., Lindquist, S. G., Hjermind, L. E., Andersen, B. B., Wallin, A., Nilsson, C., and Petersén, A. (2010) Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors. Eur J Neurol 17, 456-460
24. Lomenick, B., Jung, G., Wohlschlegel, J. A., and Huang, J. (2011) Target identification using drug affinity responsive target stability (DARTS). Curr Protoc Chem Biol 3, 163-180
25. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., and LaFerla, F. M. (2003) Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409-421
26. Morris, R. (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11, 47-60
27. Hardy, J. A., and Higgins, G. A. (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184-185
28. Faucher, P., Mons, N., Micheau, J., Louis, C., and Beracochea, D. J. (2015) Hippocampal injections of oligomeric amyloid beta-peptide (1-42) induce selective working memory deficits and long-lasting alterations of ERK signaling pathway. Front Aging Neurosci 7, 245
29. Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., and Klein, W. L. (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95, 6448-6453
30. Rowan, M. J., Klyubin, I., Wang, Q., Hu, N. W., and Anwyl, R. (2007) Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans 35, 1219-1223
31. Walsh, D. M., Klyubin, I., Shankar, G. M., Townsend, M., Fadeeva, J. V., Betts, V., Podlisny, M. B., Cleary, J. P., Ashe, K. H., Rowan, M. J., and Selkoe, D. J. (2005) The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention. Biochem Soc Trans 33, 1087-1090
32. Ostapchenko, V. G., Chen, M., Guzman, M. S., Xie, Y. F., Lavine, N., Fan, J., Beraldo, F. H., Martyn, A. C., Belrose, J. C., Mori, Y., MacDonald, J. F., Prado, V. F., Prado, M. A., and Jackson, M. F. (2015) The transient receptor potential melastatin 2 (TRPM2) channel contributes to beta-amyloid oligomer-related neurotoxicity and memory impairment. J Neurosci 35, 15157-15169
33. Diomede, L., Romeo, M., Cagnotto, A., Rossi, A., Beeg, M., Stravalaci, M., Tagliavini, F., Di Fede, G., Gobbi, M., and Salmona, M. (2016) The new beta amyloid-derived peptide Abeta1-6A2V-TAT(D) prevents Abeta oligomer formation and protects transgenic C. elegans from Abeta toxicity. Neurobiol Dis 88, 75-84
34. Thapa, A., Jett, S. D., and Chi, E. Y. (2016) Curcumin Attenuates Amyloid-beta Aggregate Toxicity and Modulates Amyloid-beta Aggregation Pathway. ACS Chem Neurosci 7, 56-68
35. Schwarzman, A. L., Gregori, L., Vitek, M. P., Lyubski, S., Strittmatter, W. J., Enghilde, J. J., Bhasin, R., Silverman, J., Weisgraber, K. H., and Coyle, P. K. (1994) Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc Natl Acad Sci U S A 91, 8368-8372
36. Velayudhan, L., Killick, R., Hye, A., Kinsey, A., Güntert, A., Lynham, S., Ward, M., Leung, R., Lourdusamy, A., To, A. W., Powell, J., and Lovestone, S. (2012) Plasma transthyretin as a candidate marker for Alzheimer's disease. J Alzheimers Dis 28, 369-375

簡易檢索 / 詳目顯示

相關論文