臺灣博碩士論文加值系統

生理上乙型類澱粉樣（Aβ）胜肽由它的前驅膜蛋白(APP)經由酵素水解而來，在不同的切位會產生不同長度的Aβ片段。其中以40個胺基酸組成的Aβ40佔絕大多數，其次則為Aβ42、Aβ43等不同的片段。由Aβ所形成的類澱粉樣纖維沉積物是阿茲海默症最明顯的病理特徵之一。文獻中，Aβ纖維具有多種不同的分子結構，且不同構型的Aβ纖維所具有的細胞毒性也不盡相同。我們認為在Aβ聚積的過程初期，不同的成核途徑（初成核、次成核等）可能會引導出不同分子結構的Aβ核種，進而生成不同構型的纖維。為了證明這點，我們嘗試在Aβ40聚合初期時，利用物理性的空間限制減緩Aβ40纖維的形成，令Aβ40核種皆來自初成核，而非與纖維有關的次成核途徑。本研究以逆向蒸發法製備包覆Aβ40單體的微脂體，在經過3－4天的培養後，我們使用對Aβ聚合物有專一性的OMAB抗體辨認，證明微脂體中形成了Aβ40的非纖維狀的核種。接著使用引晶的方式令Aβ40單體依照此核種的結構成長為纖維，並以電子顯微鏡、固態核磁共振技術鑑定纖維結構，證實經由微脂體包覆的步驟，能夠使Aβ40纖維具有幾乎單一的分子結構，初步驗證了類澱粉樣蛋白的成長過程中，最終纖維的結構也許於最初核種的形成途徑就已經決定。此外，我們也試圖以微脂體包覆Aβ42單體，並依照上述方式培養成為Aβ42的核種，並以此對Aβ40單體進行引晶實驗，目的是瞭解不同長度片段的Aβ胜肽之間是否在分子結構較為鬆散的聚合中間態可以產生交叉引晶的現象。最終的實驗結果雖然無法說明兩者在中間態的狀態下確實具有交互作用，但仍提供了一個具有潛力的方向，讓未來的研究者作為參考。  

Physiologically beta amyloid peptides (Aβ) are formed by the enzymatic cleavage of the amyloid precursor protein (APP). Depending on the cutting sites, Aβ peptides may contain 40 to 43 residues, where the 40-residue peptide (Aβ40) is the most abundant species. The plagues formed by the fibrillar aggregation of the Aβ peptides are closely associated with the progression of the AD disease. Amyloid fibrils formed by the 40-residue beta amyloid peptides (Aβ40) are highly polymorphic, with molecular structures that depend on the different kinds of nuclei. In this study, we used the method of reverse-phase evaporation to incubate the Aβ peptides in liposomes, where the peptides were either encapsulated within the liposomes or confined to the interliposomal space. From the results of the dot blot assay using the antibody OMAB, which is specific to the oligomeric aggregates of Aβ40, the Aβ40 peptides incubated in liposomes for 3 to 4 days were proven to be on-pathway non-fibrillar aggregates. These Aβ40 aggregates were used to seed the fibrillization of Aβ40 monomers, and the hence obtained fibril structures were shown to be structurally monomorphic on the basis of solid-state NMR measurements. Our results suggest that the structural polymorphism of Aβ40 may be originated from the early aggregation events of beta-amyloid peptides. In addition, we also attempted to prepare the non-fibrillar aggregates of Aβ42 by the same liposomal process to see whether they can seed the fibrillization of Aβ40 peptides. Our aim is to understand whether the nonfibrillar aggregates of Aβ42 could interact with the Aβ40 monomers. Although the preliminary results cannot unequivocally demonstrate the molecular interaction between Aβ42 and Aβ40 peptides, our approach provides a useful method to probe the possible interactions between on-pathway intermediates of different amyloidogenic peptides. 

論文口試委員審定書 i
謝誌 ii
中文摘要 v
Abstract vi
縮寫表 vii
目錄 ix
表目錄 xii
圖目錄 xiii
第一章 緒論 1
1.1 類澱粉樣蛋白纖維 1
1.2 Aβ胜肽在阿茲海默症中所扮演的角色 3
1.3 類澱粉樣蛋白質摺疊與Aβ胜肽之成核途徑 6
1.4 Aβ纖維分子結構之多樣性 10
1.5 微脂體及其製備方法之簡介 12
1.6 Aβ40胜肽與脂質膜間的交互作用 15
1.7 Aβ40與Aβ42的交互作用 20
1.8 研究動機 22
1.9 參考文獻 23
第二章 合成與鑑定 34
2.1 材料與使用儀器 34
2.2 胜肽製備 38
2.2.1 胜肽合成 38
2.2.2 胜肽純化 42
2.2.3 胜肽鑑定 43
2.3 Aβ40類澱粉樣纖維製備 44
2.4 包覆Aβ單體之微脂體製備 45
2.4.1 LipoAβ40製備—逆向蒸發法 45
2.4.2 LipoAβ40純化—粒徑篩析層析法 46
2.5 LipoAβ40-fibril製備 47
2.6 Aβ40類澱粉樣纖維及微脂體之鑑定 48
2.6.1 ThT螢光偵測 48
2.6.2 Calcein螢光偵測 50
2.6.3 穿透式電子顯微鏡 52
2.6.4 動態光散射粒徑分佈儀 54
2.6.5 斑點印迹法 56
2.7 Aβ40類澱粉樣纖維結構之鑑定—固態核磁共振光譜 58
2.7.1 核磁共振基本原理 58
2.7.2 固態核磁共振技術 59
2.8 LipoAβ42對Aβ40的引晶效果探討 61
2.9 參考文獻 62
第三章 實驗結果與討論 66
3.1 胜肽的合成、純化與鑑定 66
3.2 以微脂體包覆Aβ40單體 68
3.2.1 微脂體的鑑定 68
3.2.2 LipoAβ40之穩固度 70
3.2.3 LipoAβ40中Aβ40之含量 71
3.3 Aβ40纖維、LipoAβ40及LipoAβ40-fibril 之鑑定 74
3.3.1 Aβ40纖維的生長曲線 74
3.3.2 Aβ40在微脂體樣品中的聚合狀態 75
3.3.3 LipoAβ40的引晶效應 76
3.3.4 Aβ40纖維的螺旋間距統計 78
3.3.5 Aβ40纖維分子結構之鑑定—固態核磁共振光譜 79
3.4 以非纖維狀Aβ42聚合物對Aβ40的引晶效應探討 88
3.4.1 微脂體的鑑定 88
3.4.2 LipoAβ42中Aβ42之含量 90
3.4.3 LipoAβ42對Aβ40的引晶效應 91
3.5 結果討論 93
3.6 參考文獻 96
第四章 論文總結 98
4.1 論文結論與未來展望 98
4.2 參考文獻 101
附錄A 103
附錄B 106
附錄C 108
附錄D 110

第一章
1.Sipe, J. D. & Cohen, A. S. Review: History of the Amyloid Fibril. J. Struct. Biol. 130, 88–98 (2000).
2.Chiti, F. & Dobson, C. M. Protein Misfolding, Functional Amyloid, and Human Disease. Annu. Rev. Biochem. 75, 333–366 (2006).
3.Puchtler, H., Sweat, F. & Levine, M. ON THE BINDING OF CONGO RED BY AMYLOID. J Histochem Cytochem. 10, 355–364 (1962).
4.Serpell, L. C., Benson, M., Liepnieks, J. J. & Fraser, P. E. Structural analyses of fibrinogen amyloid fibrils. Amyloid 14, 199–203 (2007)
5.Shirahama, T. & Cohen, A. S. High-resolution Electron Microscopic Analysis of the Amyloid Fibril. J Cell Biol 33, 679–708 (1967).
6.Sunde, M. & Blake, C. The Structure of Amyloid Fibrils by Electron Microscopy and X-Ray Diffraction. Advances in Protein Chemistry 50, 123–159 (1997).
7.Astbury, W. T., Dickinson, S. & Bailey, K. The X-ray interpretation of denaturation and the structure of the seed globulins. Biochem J 29, 2351-2360.1 (1935).
8.Eanes, E. D. & Glenner, G. G. X-ray diffraction studies on amyloid filaments. J Histochem Cytochem. 16, 673–677 (1968).
9.Eisenberg, D. & Jucker, M. The Amyloid State of Proteins in Human Diseases. Cell 148, 1188–1203 (2012).
10.Gillam, J. E. & MacPhee, C. E. Modelling amyloid fibril formation kinetics: mechanisms of nucleation and growth. J. Phys. Condens. Matter 25, 373101 (2013).
11.Yamaguchi, H. et al. Alzheimer Type Dementia: Diffuse Type of Senile Plaques Demonstrated by Beta Protein Immunostaining. Prog. Clin. Biol. Res. 317, 467–474 (1989).
12.Berchtold, N. C. & Cotman, C. W. Evolution in the Conceptualization of Dementia and Alzheimer’s Disease: Greco-Roman Period to the 1960s. Neurobiology of Aging 19, 173–189 (1998).
13.Kidd, M. Alzheimer’s Disease —An Electron Microscopical Study. Brain 87, 307–320 (1964).
14.Glenner, G. G. & Wong, C. W. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).
15.Selkoe, D. J. The cell biology of β-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends in Cell Biology 8, 447–453 (1998).
16.Zhang, C. Natural Compounds That Modulate BACE1-processing of Amyloid-beta Precursor Protein in Alzheimer’s Disease. Discovery Medicine 14, 189–197 (2012).
17.Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
18.Price, J. L. & Morris, J. C. Tangles and plaques in nondemented aging and ‘preclinical’ Alzheimer’s disease. Ann. Neurol. 45, 358–368 (1999).
19.Lue, L.-F. et al. Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease. Am J Pathol 155, 853–862 (1999).
20.McLean, C. A. et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 46, 860–866 (1999).
21.Wang, J., Dickson, D. W., Trojanowski, J. Q. & Lee, V. M. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging. Exp. Neurol. 158, 328–337 (1999).
22.Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. U.S.A. 95, 6448–6453 (1998).
23.Hardy, J. & Selkoe, D. J. The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics. Science 297, 353–356 (2002).
24.Lu, J.-X. et al. Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154, (2013).
25.Mankar, S., Anoop, A., Sen, S. & Maji, S. K. Nanomaterials: amyloids reflect their brighter side. Nano Rev 2, (2011).
26.Cohen, S. I. A., Vendruscolo, M., Dobson, C. M. & Knowles, T. P. J. Nucleated Polymerisation in the Presence of Pre-Formed Seed Filaments. Int J Mol Sci 12, 5844–5852 (2011).
27.Lomakin, A., Chung, D. S., Benedek, G. B., Kirschner, D. A. & Teplow, D. B. On the nucleation and growth of amyloid beta-protein fibrils: detection of nuclei and quantitation of rate constants. Proc. Natl. Acad. Sci. U.S.A. 93, 1125–1129 (1996).
28.Lomakin, A., Teplow, D. B., Kirschner, D. A. & Benedek, G. B. Kinetic theory of fibrillogenesis of amyloid β-protein. Proc. Natl. Acad. Sci. U.S.A. 94, 7942–7947 (1997).
29.Meisl, G. et al. Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides. Proc. Natl. Acad. Sci. U.S.A. 111, 9384–9389 (2014).
30.Cukalevski, R. et al. The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation. Chem Sci 6, 4215–4233 (2015).
31.Chiti, F. & Dobson, C. M. Protein Misfolding, Functional Amyloid, and Human Disease. Annu. Rev. Biochem. 75, 333–366 (2006).
32.Meinhardt, J., Sachse, C., Hortschansky, P., Grigorieff, N. & Fändrich, M. Aβ(1-40) Fibril Polymorphism Implies Diverse Interaction Patterns in Amyloid Fibrils. J. Mol. Biol. 386, 869–877 (2009).
33.Petkova, A. T. et al. Self-Propagating, Molecular-Level Polymorphism in Alzheimer’s ß-Amyloid Fibrils. Science 307, 262–265 (2005).
34.Petkova, A. T., Yau, W.-M. & Tycko, R. Experimental constraints on quaternary structure in Alzheimer’s β-amyloid fibrils. Biochemistry 45, 498–512 (2006).
35.Paravastu, A. K., Leapman, R. D., Yau, W.-M. & Tycko, R. Molecular structural basis for polymorphism in Alzheimer’s β-amyloid fibrils. Proc. Natl. Acad. Sci. U.S.A. 105, 18349–18354 (2008).
36.Lu, J.-X. et al. Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154, (2013).
37.Bangham, A. D., Standish, M. M. & Weissmann, G. The action of steroids and streptolysin S on the permeability of phospholipid structures to cations. J. Mol. Biol. 13, 253-IN28 (1965).
38.Thulasiramaraju, T. V., Sudhakar, A. M. S., Srikanth, S. & Sivaiah, P. LIPOSOMES: A NOVEL DRUG DELIVERY SYSTEM. Int. J. Pharm. 12, (2012).
39.Bangham, A. D., Hill, M. W. & Miller, N. G. A. Preparation and Use of Liposomes as Models of Biological Membranes. in Methods in Membrane Biology 1–68 (1974).
40.Vemuri, S. & Rhodes, C. T. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv 70, 95–111 (1995).
41.Laouini, A. et al. Preparation, Characterization and Applications of Liposomes: State of the Art. J. Colloid Sci. Biotechnol. 1, 147–168 (2012).
42.Bangham, A. D., Hill, M. W. & Miller, N. G. A. Preparation and Use of Liposomes as Models of Biological Membranes. in Methods in Membrane Biology 1–68 (1974).
43.Andhale, V. A., Patil, P. R., Dhas, A. U., Chauhan, P. D. & Desai, S. V. LIPOSOME : AN EMERGING TOOL IN DRUG CARRIER SYSTEM. Int J Pharm Technol. 8, 30 (2016).
44.Szoka, F. & Papahadjopoulos, D. Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc. Natl. Acad. Sci. U.S.A. 75, 4194–4198 (1978).
45.Pidgeon, C., McNeely, S., Schmidt, T. & Johnson, J. E. Multilayered vesicles prepared by reverse-phase evaporation: liposome structure and optimum solute entrapment. Biochemistry 26, 17–29 (1987).
46.Williams, T. L. & Serpell, L. C. Membrane and surface interactions of Alzheimer’s Aβ peptide – insights into the mechanism of cytotoxicity. The FEBS Journal 278, 3905–3917 (2011).
47.Williams, T. L., Day, I. J. & Serpell, L. C. The Effect of Alzheimer’s Aβ Aggregation State on the Permeation of Biomimetic Lipid Vesicles. Langmuir 26, 17260–17268 (2010).
48.Milanesi, L. et al. Direct three-dimensional visualization of membrane disruption by amyloid fibrils. PROC. NATL. ACAD. SCI. U.S.A. 109, 20455–20460 (2012).
49.Lin, H., Bhatia, R. & Lal, R. Amyloid β protein forms ion channels: implications for Alzheimer’s disease pathophysiology. The FASEB Journal 15, 2433–2444 (2001).
50.Yanagisawa, K., Odaka, A., Suzuki, N. & Ihara, Y. GM1 ganglioside–bound amyloid β–protein (Aβ): A possible form of preamyloid in Alzheimer’s disease. Nature Medicine 1, 1062–1066 (1995).
51.Matsuzaki, K. How Do Membranes Initiate Alzheimer’s Disease? Formation of Toxic Amyloid Fibrils by the Amyloid β-Protein on Ganglioside Clusters. Acc. Chem. Res. 47, 2397–2404 (2014).
52.Matsuzaki, K. How Do Membranes Initiate Alzheimer’s Disease? Formation of Toxic Amyloid Fibrils by the Amyloid β-Protein on Ganglioside Clusters. Acc. Chem. Res. 47, 2397–2404 (2014).
53.Niu, Z. et al. The Molecular Structure of Alzheimer β-Amyloid Fibrils Formed in the Presence of Phospholipid Vesicles. Angewandte Chemie International Edition 53, 9294–9297 (2014).
54.Chi, E. Y. et al. Lipid membrane templates the ordering and induces the fibrillogenesis of Alzheimer’s disease amyloid-β peptide. Proteins 72, 1–24 (2008).
55.Sabaté, R., Espargaró, A., Barbosa-Barros, L., Ventura, S. & Estelrich, J. Effect of the surface charge of artificial model membranes on the aggregation of amyloid β-peptide. Biochimie 94, 1730–1738 (2012).
56.Chauhan, A., Ray, I. & Chauhan, V. P. Interaction of amyloid beta-protein with anionic phospholipids: possible involvement of Lys28 and C-terminus aliphatic amino acids. Neurochem. Res. 25, 423–429 (2000).
57.Delgado, D. A. et al. Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides. J. Biol. Chem. 291, 12233–12244 (2016).
58.Terzi, E., Hölzemann, G. & Seelig, J. Interaction of Alzheimer β-Amyloid Peptide(1−40) with Lipid Membranes. Biochemistry 36, 14845–14852 (1997).
59.Gravina, S. A. et al. Amyloid β Protein (Aβ) in Alzheimeri’s Disease Brain BIOCHEMICAL AND IMMUNOCYTOCHEMICAL ANALYSIS WITH ANTIBODIES SPECIFIC FOR FORMS ENDING AT Aβ40 OR Aβ42(43). J. Biol. Chem. 270, 7013–7016 (1995).
60.Iwatsubo, T. et al. Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: Evidence that an initially deposited species is Aβ42(43). Neuron 13, 45–53 (1994).
61.Roher, A. E. et al. beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 90, 10836–10840 (1993).
62.Murakami, K. et al. Neurotoxicity and Physicochemical Properties of Aβ Mutant Peptides from Cerebral Amyloid Angiopathy IMPLICATION FOR THE PATHOGENESIS OF CEREBRAL AMYLOID ANGIOPATHY AND ALZHEIMER’S DISEASE. J. Biol. Chem. 278, 46179–46187 (2003).
63.Selkoe, D. J. Alzheimer’s Disease: Genes, Proteins, and Therapy. Physiological Reviews 81, 741–766 (2001).
64.Cukalevski, R. et al. The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation. Chem. Sci. 6, 4215–4233 (2015).
65.Xiao, Y. et al. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease. Nat Struct Mol Biol 22, 499–505 (2015).
66.Tycko, R. Alzheimer’s disease: Structure of aggregates revealed. Nature 537, 492–493 (2016).
第二章
1.Patel, R. MALDI-TOF MS for the Diagnosis of Infectious Diseases. Clinical Chemistry 61, 100–111 (2015).
2.Stine, W. B., Dahlgren, K. N., Krafft, G. A. & LaDu, M. J. In Vitro Characterization of Conditions for Amyloid-β Peptide Oligomerization and Fibrillogenesis. J. Biol. Chem. 278, 11612–11622 (2003).
3.Gill, S. C. & von Hippel, P. H. Calculation of protein extinction coefficients from amino acid sequence data. Analytical Biochemistry 182, 319–326 (1989).
4.Striegel, A., Yau, W. W., Kirkland, J. J. & Bly, D. D. Modern Size-Exclusion Liquid Chromatography: Practice of Gel Permeation and Gel Filtration Chromatography. (2009).
5.Biancalana, M. & Koide, S. Molecular Mechanism of Thioflavin-T Binding to Amyloid Fibrils. Biochim Biophys Acta 1804, 1405–1412 (2010).
6.LeVine, H. Quantification of β-sheet amyloid fibril structures with thioflavin T. in Methods in Enzymology, 274–284 (1999).
7.Tsao, Y. S. & Huang, L. Sendai virus induced leakage of liposomes containing gangliosides. Biochemistry 24, 1092–1098 (1985).
8.Sun, C.-S. et al. The Influence of Pathological Mutations and Proline Substitutions in TDP-43 Glycine-Rich Peptides on Its Amyloid Properties and Cellular Toxicity. PLOS ONE 9, e103644 (2014).
9.CIC bioGUNE Electron Microscopy Platform Service - Specimen Preparation. Available at: http://personal.cicbiogune.es/dcarton/specimen.html.
10.PLASMA CLEANING - JESAGI HANKOOK. Available at: https://jesagi.en.ecplaza.net/products/plasma-cleaning_111807.
11.Zetasizer Nano user manual. (2004). Available at: http://www.biophysics.bioc.cam.ac.uk/files/Zetasizer_Nano_user_manual_Man0317-1.1.pdf.
12.Dynamic Light Scattering for Nanoparticle Size Analysis - HORIBA. Available at: http://www.horiba.com/scientific/products/particle-characterization/technology/dynamic-light-scattering/.
13.Havel, T. F. & Wüthrich, K. An evaluation of the combined use of nuclear magnetic resonance and distance geometry for the determination of protein conformations in solution. J. Mol. Biol. 182, 281–294 (1985).
14.Sunde, M. et al. Common core structure of amyloid fibrils by synchrotron X-ray diffraction11Edited by F. E. Cohen. J. Mol. Biol. 273, 729–739 (1997).
15.Franks, W. T. et al. Magic-Angle Spinning Solid-State NMR Spectroscopy of the β1 Immunoglobulin Binding Domain of Protein G (GB1):  15N and 13C Chemical Shift Assignments and Conformational Analysis. J. Am. Chem. Soc. 127, 12291–12305 (2005).
16.Schaefer, J. & Stejskal, E. O. Carbon-13 nuclear magnetic resonance of polymers spinning at the magic angle. J. Am. Chem. Soc. 98, 1031–1032 (1976).
17.Hartmann, S. R. & Hahn, E. L. Nuclear Double Resonance in the Rotating Frame. Phys. Rev. 128, 2042–2053 (1962).
18.Takegoshi, K., Nakamura, S. & Terao, T. 13C–1H dipolar-driven 13C–13C recoupling without 13C rf irradiation in nuclear magnetic resonance of rotating solids. J. Chem. Phys. 118, 2325–2341 (2003).
19.Takegoshi, K., Nakamura, S. & Terao, T. 13C–1H dipolar-assisted rotational resonance in magic-angle spinning NMR. Chem. Phys. Lett. 344, 631–637 (2001).
第三章
1.Meinhardt, J., Sachse, C., Hortschansky, P., Grigorieff, N. & Fändrich, M. Aβ(1-40) Fibril Polymorphism Implies Diverse Interaction Patterns in Amyloid Fibrils. J. Mol. Biol. 386, 869–877 (2009).
2.Petkova, A. T. et al. Self-Propagating, Molecular-Level Polymorphism in Alzheimer’s ß-Amyloid Fibrils. Science 307, 262–265 (2005).
3.Petkova, A. T., Yau, W.-M. & Tycko, R. Experimental constraints on quaternary structure in Alzheimer’s β-amyloid fibrils. Biochemistry 45, 498–512 (2006).
4.Paravastu, A. K., Leapman, R. D., Yau, W.-M. & Tycko, R. Molecular structural basis for polymorphism in Alzheimer’s β-amyloid fibrils. Proc. Natl. Acad. Sci. U.S.A. 105, 18349–18354 (2008).
5.Williams, T. L. & Serpell, L. C. Membrane and surface interactions of Alzheimer’s Aβ peptide – insights into the mechanism of cytotoxicity. The FEBS Journal 278, 3905–3917 (2011).
6.Yang, F. et al. Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo. J. Biol. Chem. 280, 5892–5901 (2005).
7.Terzi, E., Hölzemann, G. & Seelig, J. Self-association of β-Amyloid Peptide (1–40) in Solution and Binding to Lipid Membranes. J. Mol. Biol. 252, 633–642 (1995).
8.Moores, B., Drolle, E., Attwood, S. J., Simons, J. & Leonenko, Z. Effect of Surfaces on Amyloid Fibril Formation. PLoS One 6, (2011).
第四章
1.Harper, J. D., Wong, S. S., Lieber, C. M. & Lansbury, P. T. Observation of metastable Aβ amyloid protofibrils by atomic force microscopy. Chem. Biol. 4, 119–125 (1997).
2.Hartley, D. M. et al. Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons. J. Neurosci. 19, 8876–8884 (1999).
3.Benilova, I., Karran, E. & Strooper, B. D. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat. Neurosci. 15, 349–357 (2012).
4.Qiang, W., Kelley, K. & Tycko, R. Polymorph-Specific Kinetics and Thermodynamics of β-Amyloid Fibril Growth. J. Am. Chem. Soc. 135, 6860–6871 (2013).
5.Paravastu, A. K., Leapman, R. D., Yau, W.-M. & Tycko, R. Molecular structural basis for polymorphism in Alzheimer’s β-amyloid fibrils. Proc. Natl. Acad. Sci. U.S.A. 105, 18349–18354 (2008).
6.Xiao, Y. et al. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease. Nat Struct Mol Biol 22, 499–505 (2015).
7.Cukalevski, R. et al. The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation. Chem. Sci. 6, 4215–4233 (2015).
附錄
1.EANES, E. D. & GLENNER, G. G. X-RAY DIFFRACTION STUDIES ON AMYLOID FILAMENTS. J Histochem Cytochem. 16, 673–677 (1968).
2.NanoSciences, E. Liposome size calculation. (2015).
3.Predicting the fate of liposomes. (2014).
4.Schladitz, C., Vieira, E. P., Hermel, H. & Möhwald, H. Amyloid–β-Sheet Formation at the Air-Water Interface. Biophys. J. 77, 3305–3310 (1999).
5.Nichols, M. R., Moss, M. A., Reed, D. K., Hoh, J. H. & Rosenberry, T. L. Rapid Assembly of Amyloid-β Peptide at a Liquid/Liquid Interface Produces Unstable β-Sheet Fibers. Biochemistry 44, 165–173 (2005).
6.Stine, W. B., Dahlgren, K. N., Krafft, G. A. & LaDu, M. J. In Vitro Characterization of Conditions for Amyloid-β Peptide Oligomerization and Fibrillogenesis. J. Biol. Chem. 278, 11612–11622 (2003).
7.Yates, E. A. & Legleiter, J. Preparation Protocols of Aβ(1–40) Promote the Formation of Polymorphic Aggregates and Altered Interactions with Lipid Bilayers. Biochemistry 53, 7038–7050 (2014).