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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 孔繁璐(Fan-Lu Kung) | |
| dc.contributor.author | Yin-Ting Shih | en |
| dc.contributor.author | 施尹婷 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:51:39Z | - |
| dc.date.available | 2019-10-20 | |
| dc.date.copyright | 2014-10-20 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-22 | |
| dc.identifier.citation | 1. Terry, R. D.; Davies, P., Dementia of the Alzheimer Type. Annual Review of Neuroscience 1980, 3 (1), 77-95.
2. Stelzmann, R. A.; Norman Schnitzlein, H.; Reed Murtagh, F., An english translation of alzheimer's 1907 paper, “uber eine eigenartige erkankung der hirnrinde”. Clinical Anatomy 1995, 8 (6), 429-431. 3. Williamson, J.; LaRusse, S., Genetics and genetic counseling: Recommendations for Alzheimer’s disease, frontotemporal dementia, and Creutzfeldt-Jakob disease. Current Neurology and Neuroscience Reports 2004, 4 (5), 351-357. 4. Wenk, G. L., Neuropathologic changes in Alzheimer's disease. The Journal of clinical psychiatry 2003, 64 Suppl 9, 7-10. 5. Michel, G., Tau protein and neurodegeneration. Seminars in Cell & Developmental Biology 2004, 15 (1), 45-49. 6. O'Brien, R. J.; Wong, P. C., Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 2011, 34, 185-204. 7. Glenner, G. G.; Wong, C. W., Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical Research Communications 1984, 120 (3), 885-890. 8. Khalifa, N. B.; Hees, J. V.; Tasiaux, B.; Huysseune, S.; Smith, S. O.; Constantinescu, S. N.; Octave, J.-N.; Kienlen-Campard, P., What is the role of amyloid precursor protein dimerization? Cell Adhesion & Migration 2010, 4 (2), 268-272. 9. Multhaup, G., Amyloid Precursor Protein and BACE Function as Oligomers. Neurodegenerative Diseases 2006, 3 (4-5), 270-274. 10. Kitaguchi, N.; Takahashi, Y.; Tokushima, Y.; Shiojiri, S.; Ito, H., Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature 1988, 331 (6156), 530-532. 11. Buxbaum, J. D.; Gandy, S. E.; Cicchetti, P.; Ehrlich, M. E.; Czernik, A. J.; Fracasso, R. P.; Ramabhadran, T. V.; Unterbeck, A. J.; Greengard, P., Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proceedings of the National Academy of Sciences 1990, 87 (15), 6003-6006. 12. Haass, C.; Koo, E. H.; Mellon, A.; Hung, A. Y.; Selkoe, D. J., Targeting of cell-surface [beta]-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 1992, 357 (6378), 500-503. 13. Storey; Cappai, The amyloid precursor protein of Alzheimer’s disease and the Aβ peptide. Neuropathology and Applied Neurobiology 1999, 25 (2), 81-97. 14. Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G., Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis. Science 2003, 300 (5618), 486-489. 15. Vetrivel, K. S.; Thinakaran, G., Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology 2006, 66 (2 Suppl 1), S69-73. 16. Cordy, J. M.; Hussain, I.; Dingwall, C.; Hooper, N. M.; Turner, A. J., Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America 2003, 100 (20), 11735-40. 17. Simons, K.; Ikonen, E., Functional rafts in cell membranes. Nature 1997, 387 (6633), 569-572. 18. Corder, E.; Saunders, A.; Strittmatter, W.; Schmechel, D.; Gaskell, P.; Small, G.; Roses, A.; Haines, J.; Pericak-Vance, M., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993, 261 (5123), 921-923. 19. Hardy, J. A.; Mann, D. M.; Wester, P.; Winblad, B., An integrative hypothesis concerning the pathogenesis and progression of Alzheimer's disease. Neurobiology of Aging 1986, 7 (6), 489-502. 20. Evans, R. M.; Hui, S.; Perkins, A.; Lahiri, D. K.; Poirier, J.; Farlow, M. R., Cholesterol and APOE genotype interact to influence Alzheimer disease progression. Neurology 2004, 62 (10), 1869-1871. 21. Umeda, T.; Tomiyama, T.; Kitajima, E.; Idomoto, T.; Nomura, S.; Lambert, M. P.; Klein, W. L.; Mori, H., Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice. Life Sciences 2012, 91 (23–24), 1169-1176. 22. Wolozin, B.; Kellman, W.; Ruosseau, P.; Celesia, G. G.; Siegel, G., Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme a reductase inhibitors. Archives of Neurology 2000, 57 (10), 1439-1443. 23. Kurata, T.; Miyazaki, K.; Kozuki, M.; Panin, V. L.; Morimoto, N.; Ohta, Y.; Nagai, M.; Ikeda, Y.; Matsuura, T.; Abe, K., Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice. Brain Research 2011, 1371 (0), 161-170. 24. Schneider, A.; Schulz-Schaeffer, W.; Hartmann, T.; Schulz, J. B.; Simons, M., Cholesterol depletion reduces aggregation of amyloid-beta peptide in hippocampal neurons. Neurobiology of Disease 2006, 23 (3), 573-577. 25. Frears, E. R.; Stephens, D. J.; Walters, C. E.; Davies, H.; Austen, B. M., The role of cholesterol in the biosynthesis of β‐amyloid. NeuroReport 1999, 10 (8), 1699-1705. 26. Grimm, M. O. W.; Grimm, H. S.; Tomic, I.; Beyreuther, K.; Hartmann, T.; Bergmann, C., Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels. Journal of Biological Chemistry 2008, 283 (17), 11302-11311. 27. Fassbender, K.; Simons, M.; Bergmann, C.; Stroick, M.; Lutjohann, D.; Keller, P.; Runz, H.; Kuhl, S.; Bertsch, T.; von Bergmann, K.; Hennerici, M.; Beyreuther, K.; Hartmann, T., Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo. Proceedings of the National Academy of Sciences 2001, 98 (10), 5856-5861. 28. Kojro, E.; Gimpl, G.; Lammich, S.; Marz, W.; Fahrenholz, F., Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proceedings of the National Academy of Sciences 2001, 98 (10), 5815-5820. 29. Munter, L. M.; Voigt, P.; Harmeier, A.; Kaden, D.; Gottschalk, K. E.; Weise, C.; Pipkorn, R.; Schaefer, M.; Langosch, D.; Multhaup, G., GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42. The EMBO journal 2007, 26 (6), 1702-12. 30. Kienlen-Campard, P.; Tasiaux, B.; Van Hees, J.; Li, M.; Huysseune, S.; Sato, T.; Fei, J. Z.; Aimoto, S.; Courtoy, P. J.; Smith, S. O.; Constantinescu, S. N.; Octave, J.-N., Amyloidogenic Processing but Not Amyloid Precursor Protein (APP) Intracellular C-terminal Domain Production Requires a Precisely Oriented APP Dimer Assembled by Transmembrane GXXXG Motifs. Journal of Biological Chemistry 2008, 283 (12), 7733-7744. 31. Gralle, M.; Oliveira, C. L. P.; Guerreiro, L. H.; McKinstry, W. J.; Galatis, D.; Masters, C. L.; Cappai, R.; Parker, M. W.; Ramos, C. H. I.; Torriani, I.; Ferreira, S. T., Solution Conformation and Heparin-induced Dimerization of the Full-length Extracellular Domain of the Human Amyloid Precursor Protein. Journal of Molecular Biology 2006, 357 (2), 493-508. 32. Scheuermann, S.; Hambsch, B.; Hesse, L.; Stumm, J.; Schmidt, C.; Beher, D.; Bayer, T. A.; Beyreuther, K.; Multhaup, G., Homodimerization of Amyloid Precursor Protein and Its Implication in the Amyloidogenic Pathway of Alzheimer's Disease. Journal of Biological Chemistry 2001, 276 (36), 33923-33929. 33. Permanne, B.; Perez, C.; Soto, C.; Frangione, B.; Wisniewski, T., Detection of Apolipoprotein E/Dimeric Soluble Amyloid β Complexes in Alzheimer's Disease Brain Supernatants. Biochemical and Biophysical Research Communications 1997, 240 (3), 715-720. 34. Ishitsuka, R.; Kobayashi, T., Cholesterol and Lipid/Protein Ratio Control the Oligomerization of a Sphingomyelin-Specific Toxin, Lysenin†. Biochemistry 2007, 46 (6), 1495-1502. 35. Dainese, E.; Oddi, S.; Maccarrone, M., Lipid-mediated dimerization of beta2-adrenergic receptor reveals important clues for cannabinoid receptors. Cell Mol Life Sci 2008, 65 (15), 2277-9. 36. Epand, R. M., Cholesterol and the interaction of proteins with membrane domains. Progress in Lipid Research 2006, 45 (4), 279-294. 37. Mok, S. S.; Sberna, G.; Heffernan, D.; Cappai, R.; Galatis, D.; Clarris, H. J.; Sawyer, W. H.; Beyreuther, K.; Masters, C. L.; Small, D. H., Expression and analysis of heparin-binding regions of the amyloid precursor protein of Alzheimer's disease. FEBS Letters 1997, 415 (3), 303-307. 38. Kaden, D.; Munter, L. M.; Reif, B.; Multhaup, G., The amyloid precursor protein and its homologues: Structural and functional aspects of native and pathogenic oligomerization. European Journal of Cell Biology 2012, 91 (4), 234-239. 39. Beckman, M.; Holsinger, R. M. D.; Small, D. H., Heparin Activates β-Secretase (BACE1) of Alzheimer's Disease and Increases Autocatalysis of the Enzyme. Biochemistry 2006, 45 (21), 6703-6714. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57563 | - |
| dc.description.abstract | 阿茲海默症 (Alzheimer’s disease, AD) 是一種漸進式的神經退化疾病，其病徵之一為APP蛋白經連續性酵素水解後產生的Aβ堆積。許多研究證實膽固醇在AD的病程發展上扮演著重要的角色，但其詳細作用機轉則仍未釐清。我們初步的研究發現膽固醇與APP產生交互作用可能會影響APP在膜上的分布，進而影響其水解。
在本研究中，我們將APP上的CRAC序列以點突變的方式略作改變，試圖藉由觀察這些mutants和wild-type APP在膽固醇結合、二聚體形成、及APP processing上之差異，來釐清APP與膽固醇交互作用在APP水解中扮演的角色。結果顯示在5種APP mutants中，只有APPS622L與膽固醇的結合程度比wild-type APP低，並觀察到其C99/C83比值下降，因而推測膽固醇與APP JM/TM區段之作用可能會影響APP之水解；APPY422F與APPY422L與膽固醇結合程度的差異則可能與APP heparin domain (HBD2) 中的helix-helix結構之穩定性相關，而此結構的瓦解與否也可能會影響APP形成二聚體，進而改變APP水解路徑；至於APPY463I，其與膽固醇的結合程度較wild-type APP為高，同時dimer/monomer之比值也較高，可能是因為Y463位於helix-helix結構之外側，較為solvent accessible，不須破壞前述之helix-helix結構即可與膽固醇結合，因此推測除helix-helix結構可能對二聚體的形成有一些幫助之外，膽固醇之結合可能會有助於誘使APP形成二聚體，進而促使APP經由amyloidogenic pathway代謝。此研究發現位在近膜區的CRAC序列可能是與膽固醇產生交互作用的重要片段，而膽固醇可能可以以不同的方式影響APP形成二聚體、或是將APP帶到raft上，走向amyloidogenic pathway。 | zh_TW |
| dc.description.abstract | Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. One of the histopathological features of AD is the extracellular aggregation of amyloid β (Aβ) derived from amyloid precursor protein (APP) processing. Previous studies have indicated that cholesterol plays an important role in the pathogenesis of AD. However, the exactly regulatory mechanism is not yet clearly known. Our preliminary studies revealed that the interaction between cholesterol and APP might affect APP distribution, leading to altered APP processing.
To elucidate the roles of cholesterol-binding in APP processing, The cholesterol- binding and dimer formation properties and processing patterns of various APP mutants (i.e., with disrupted potential cholesterol recognition amino acid consensus (CRAC) motif) generated via site-directed mutagenesis were compared with wild-type APP. Among all 5 mutants, only APPS622L appeared to have a lower cholesterol binding capacity and a lower C99/C83 ratio compared with wild-type. It is therefore suspected that the interaction between cholesterol and the APP JM/TM region may affect APP processing. The difference in cholesterol-binding capacity between APPY422F and APPY422L seems to be associated with the stability of the helix-helix structure in the heparin binding domain (HBD2) of APP, which may contribute to APP dimerization. APPY463I, on the other hand, has a higher binding capacity and a higher dimer/monomer ratio than wild-type. Since Y463 is positioned at the solvent accessible surface of the aforementioned helix-helix structure, it is possible that APPY463I is able to interact with cholesterol without disrupting its helix-helix structure. Both cholesterol-binding and a more stable helix-helix structure may contribute to the observed higher dimer/monomer ratio in the APPY463I mutant, which in turn leads to a shift towards the amyloidogenic pathway. In conclusion, results from this study indicate that the CRAC motif in the JM/TM region of APP may play a crucial role in cholesterol-APP interaction, and that cholesterol may affect APP dimerization, translocation, and processing through different kinds of mechanisms. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:51:39Z (GMT). No. of bitstreams: 1 ntu-103-R00423024-1.pdf: 2112039 bytes, checksum: dd959360f8882bdc7955ebef8bf2ecf0 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
誌謝 II 中文摘要 III 英文摘要 IV 英文縮寫表 V 目錄 VI 序論 1 研究目的 6 實驗方法 7 實驗結果與討論 16 1、找出膽固醇與APP蛋白交互作用的重要位置 16 2、特定位置上的mutation在APP dimerization中扮演的角色 19 3、特定位置上的mutation在APP processing中扮演的角色 22 圖表說明 26 參考文獻 38 | |
| dc.language.iso | zh-TW | |
| dc.subject | APP二聚體 | zh_TW |
| dc.subject | 膽固醇 | zh_TW |
| dc.subject | APP蛋白水解 | zh_TW |
| dc.subject | cholesterol | en |
| dc.subject | APP processing | en |
| dc.subject | APP dimerization | en |
| dc.title | 探討膽固醇與APP蛋白間之交互作用對APP蛋白水解之影響 | zh_TW |
| dc.title | Investigation of the Effects of APP-Cholesterol Interaction on APP processing | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顧紀華(Jih-Hwa Guh),許麗卿(Lih-Ching Hsu) | |
| dc.subject.keyword | 膽固醇,APP蛋白水解,APP二聚體, | zh_TW |
| dc.subject.keyword | cholesterol,APP processing,APP dimerization, | en |
| dc.relation.page | 41 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-22 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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