臺灣博碩士論文加值系統

根據實驗指出，Aβ43蛋白在阿茲海默氏症扮演重要的角色，並且比Aβ40與Aβ42更容易引發聚集形成斑塊（plaque）而損壞神經元，使得神經細胞死亡進而導致患者發病。由於Aβ43結構尚未定義清楚，為了找出Aβ43最佳結構，本論文利用模擬退火法在水溶液中將Aβ43蛋白從常溫逐步升溫至500K，最後降溫至常溫，篩選出5個能量最低的結構，在進行常溫不同酸鹼值環境下長時間分子動力學模擬。從結構穩定度分析中RMSD和Rg曲線穩定後，在經由蛋白質-蛋白質交互作用能量（Protein-Protein Interaction Energy）的分析，選取能量最低的時間點對照在主成分分析（Principal Component Analysis；PCA）分析密集中找出4種Aβ43最可能的構型，結構共同特性在殘基片段10-17為α-helix結構，可做為未來研究Aβ43結構參考。

Amyloid beta(Aβ) is a major cause of Alzheimer's disease. There are three major forms of Aβ producing 40,42 and 43 residues long, accumulating and depositing in our brain forming protein amyloid plaques. Neuros would be damaged by this deposition.Accroding to the experiment in Alzheimer's disease, the previous researches show that the amyloid plaque of Aβ43 is more frequent and toxic than the other two, however, the structure of Aβ43 is not clear enough ,in order to expore this out. In this thesis, Aβ43 was simulated from 300K to 500K in aqueous solution under simulated annealing method. We select five possible candiates after the temperature drops to 300K. Sequentially, the five candiates were simulated under different pH values in room temperature during 80ns by using molecular dynamics. With the stable analysis of RMSD and Rg, we find out four probable conformers which has similar structural charasteristics of α-helix,segment 10-17, compared with Protein-Protein Interaction Energy and Principal component analysis in local minimum energy.These findings provide a data base for the future research.

中文摘要 I
Abstract II
致謝 III
目錄 IV
表目錄 VI
圖目錄 VII
符號說明 XII
第一章 緒論 1
1-1 本文架構 1
1-2 阿茲海默式症介紹 2
1-3 阿茲海默氏症病理特徵 6
1-4 阿茲海默氏症與血管型失智症比較 9
1-5 阿茲海默氏症病因 11
1-6 阿茲海默氏症用藥及方法 15
第二章 類澱粉蛋白 26
2-1 老化斑塊和類澱粉（Senile Plaques and Amyloid) 26
2-2 Aβ神經病理學 31
2-3 澱粉樣蛋白假說（Amyloid Hypothesis） 34
2-4 文獻回顧 36
2-5 研究動機與目的 44
第三章 分子動力學與模擬方法 46
3-1 軟體介紹 46
3-2 Abeta43建模過程 50
3-3 模擬退火法 57
3-4 分子動力學模擬方法 64
3-5 Gromacs模擬流程 74
3-6 Gromacs模擬步驟 75
3-7 粗粒化模擬建構方法與介紹 84
第四章 結果與討論 89
4-1 均方根誤差（Root Mean Square Derivation；RMSD）分析 89
4-2 迴轉半徑（Radius of gyration；Rg） 93
4-3 均方根波動（Root Mean Square Fluctuation；RMSF） 97
4-4 氫鍵分析（Hydrogen Bond） 100
4-5 親疏水分析（Slvent Acessible Srface Aea）105
4-6 特徵值分析（Eigenvalue） 112
4-7 斜方差矩陣分析（covariance） 114
4-8 主成分分析（Principal Component Analysis；PCA） 118
4-9 蛋白質-蛋白質能量（Protein-Protein Interaction Energy） 127
4-10 二級結構分析（Define Secondary Structure of Proteins） 132
第五章 結論 136
第六章 未來展望及建議 139
參考文獻 141

[1]W. L. Klein, G. A. Krafft, and C. E. Finch, Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?, Trends Neurosci, vol. 24, pp. 219-24, Apr 2001.
[2]C. L. Masters and K. Beyreuther, Alzheimer's disease, BMJ, vol. 316, pp. 446-8, Feb 7 1998.
[3]L. Mucke, Neuroscience: Alzheimer's disease, Nature, vol. 461, pp. 895-7, Oct 15 2009.
[4]http://www.genome.jp/dbget-bin/www_bget?map05010.
[5]M. Bedard, D. W. Molloy, T. Standish, G. H. Guyatt, J. Dsouza, C. Mondadori, et al., Clinical-Trials in Cognitively Impaired Older Adults - Home Versus Clinic Assessments, Journal of the American Geriatrics Society, vol. 43, pp. 1127-1130, Oct 1995.
[6]R. N. Rosenberg, R. W. Richter, R. C. Risser, K. Taubman, I. Prado-Farmer, E. Ebalo, et al., Genetic factors for the development of Alzheimer disease in the Cherokee Indian, Arch Neurol, vol. 53, pp. 997-1000, Oct 1996.
[7]S. T. DeKosky, Managing Alzheimer's disease, Neurology, vol. 48, pp. S1-S1, May 1997.
[8]D. I. Kaufer, Cholinesterase-inhibitor therapy for dementia: novel clinical substrates and mechanisms for treatment response, CNS Spectr, vol. 7, pp. 742-50, Oct 2002.
[9]N. Pantchev, D. Gassmann, and M. Globokar-Vrhovec, Increasing numbers of Giardia (but not coccidian) infections in ferrets, 2002 to 2010, Veterinary Record, vol. 168, May 14 2011.
[10]R. C. Mohs, R. S. Doody, J. C. Morris, J. R. Ieni, S. L. Rogers, C. A. Perdomo, et al., A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients, Neurology, vol. 57, pp. 481-488, Aug 14 2001.
[11]F. Inglis, The tolerability and safety of cholinesterase inhibitors in the treatment of dementia, International Journal of Clinical Practice, pp. 45-63, Jun 2002.
[12]R. Blesa, R. Bullock, Y. He, H. Bergman, G. Gambina, J. Meyer, et al., Effect of butyrylcholinesterase genotype on the response to rivastigmine or donepezil in younger patients with Alzheimer's disease, Pharmacogenet Genomics, vol. 16, pp. 771-4, Nov 2006.
[13]R. Bullock and R. Lane, Executive dyscontrol in dementia, with emphasis on subcortical pathology and the role of butyrylcholinesterase, Curr Alzheimer Res, vol. 4, pp. 277-93, Jul 2007.
[14]R. Bullock, J. Touchon, H. Bergman, G. Gambina, Y. He, G. Rapatz, et al., Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period, Curr Med Res Opin, vol. 21, pp. 1317-27, Aug 2005.
[15]P. Bentham, R. Gray, E. Sellwood, and J. Raftery, Effectiveness of rivastigmine in Alzheimer's disease. Improvements in functional ability remain unestablished, BMJ, vol. 319, pp. 640-1, Sep 4 1999.
[16]A. McCaddon, P. Hudson, G. Davies, A. Hughes, J. H. Williams, and C. Wilkinson, Homocysteine and cognitive decline in healthy elderly, Dement Geriatr Cogn Disord, vol. 12, pp. 309-13, Sep-Oct 2001.
[17]B. Winblad, G. Grossberg, L. Frolich, M. Farlow, S. Zechner, J. Nagel, et al., IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease, Neurology, vol. 69, pp. S14-22, Jul 24 2007.
[18]B. Winblad, J. Cummings, N. Andreasen, G. Grossberg, M. Onofrj, C. Sadowsky, et al., A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease--rivastigmine patch versus capsule, Int J Geriatr Psychiatry, vol. 22, pp. 456-67, May 2007.
[19]J. Corey-Bloom, The efficacy and safety of ENA-713 in patients with mild to moderately severe Alzheimer's disease, Journal of the American Geriatrics Society, vol. 46, pp. S12-S12, Sep 1998.
[20]S. Gauthier, Advances in the pharmacotherapy of Alzheimer's disease, Canadian Medical Association Journal, vol. 166, pp. 616-623, Mar 5 2002.
[21]P. N. Tariot, P. R. Solomon, J. C. Morris, P. Kershaw, S. Lilienfeld, and C. Ding, A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group, Neurology, vol. 54, pp. 2269-76, Jun 27 2000.
[22]J. M. Lopez-Arrieta and L. Schneider, Metrifonate for Alzheimer's disease, Cochrane Database Syst Rev, p. CD003155, 2006.
[23]C. M. Bird and N. Burgess, The hippocampus and memory: insights from spatial processing, Nat Rev Neurosci, vol. 9, pp. 182-94, Mar 2008.
[24]P. Mavrogiorgou, H. J. Gertz, R. Ferszt, R. Wolf, K. J. Bar, and G. Juckel, Are routine methods good enough to stain senile plaques and neurofibrillary tangles in different brain regions of demented patients?, Psychiatr Danub, vol. 23, pp. 334-9, Dec 2011.
[25]C. Lamy, C. Duyckaerts, P. Delaere, C. Payan, J. Fermanian, V. Poulain, et al., Comparison of seven staining methods for senile plaques and neurofibrillary tangles in a prospective series of 15 elderly patients, Neuropathol Appl Neurobiol, vol. 15, pp. 563-78, Nov-Dec 1989.
[26]D. M. Walsh and D. J. Selkoe, Deciphering the molecular basis of memory failure in Alzheimer's disease, Neuron, vol. 44, pp. 181-93, Sep 30 2004.
[27]V. Wilquet and B. De Strooper, Amyloid-beta precursor protein processing in neurodegeneration, Curr Opin Neurobiol, vol. 14, pp. 582-8, Oct 2004.
[28]P. B. Olkhanud, M. Mughal, K. Ayukawa, E. Malchinkhuu, M. Bodogai, N. Feldman, et al., DNA immunization with HBsAg-based particles expressing a B cell epitope of amyloid beta-peptide attenuates disease progression and prolongs survival in a mouse model of Alzheimer's disease, Vaccine, vol. 30, pp. 1650-8, Feb 21 2012.
[29]T. Jonsson, J. K. Atwal, S. Steinberg, J. Snaedal, P. V. Jonsson, S. Bjornsson, et al., A mutation in APP protects against Alzheimer's disease and age-related cognitive decline, Nature, vol. 488, pp. 96-9, Aug 2 2012.
[30]G. Di Fede, M. Catania, M. Morbin, G. Rossi, S. Suardi, G. Mazzoleni, et al., A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis, Science, vol. 323, pp. 1473-7, Mar 13 2009.
[31]B. De Strooper and T. Voet, Alzheimer's disease: A protective mutation, Nature, vol. 488, pp. 38-9, Aug 2 2012.
[32]D. Morgan, D. M. Diamond, P. E. Gottschall, K. E. Ugen, C. Dickey, J. Hardy, et al., A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease, Nature, vol. 408, pp. 982-5, Dec 21-28 2000.
[33]C. Janus, J. Pearson, J. McLaurin, P. M. Mathews, Y. Jiang, S. D. Schmidt, et al., A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease, Nature, vol. 408, pp. 979-82, Dec 21-28 2000.
[34]F. Bard, C. Cannon, R. Barbour, R. L. Burke, D. Games, H. Grajeda, et al., Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease, Nat Med, vol. 6, pp. 916-9, Aug 2000.
[35]R. Kisilevsky, L. J. Lemieux, P. E. Fraser, X. Kong, P. G. Hultin, and W. A. Szarek, Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease, Nat Med, vol. 1, pp. 143-8, Feb 1995.
[36]P. E. Fraser, A. A. Darabie, and J. A. McLaurin, Amyloid-beta interactions with chondroitin sulfate-derived monosaccharides and disaccharides. implications for drug development, J Biol Chem, vol. 276, pp. 6412-9, Mar 2 2001.
[37]S. S. Sisodia and P. H. St George-Hyslop, gamma-Secretase, notch, A beta and Alzheimer's disease: Where do the presenilins fit in?, Nature Reviews Neuroscience, vol. 3, pp. 281-290, Apr 2002.
[38]G. L. Wenk, Neuropathologic changes in Alzheimer's disease, Journal of Clinical Psychiatry, vol. 64, pp. 7-10, 2003.
[39]H. Braak and K. Del Tredici, Where, when, and in what form does sporadic Alzheimer's disease begin?, Current Opinion in Neurology, vol. 25, pp. 708-714, Dec 2012.
[40]R. S. Desikan, H. J. Cabral, C. P. Hess, W. P. Dillon, C. M. Glastonbury, M. W. Weiner, et al., Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease, Brain, vol. 132, pp. 2048-57, Aug 2009.
[41]H. I. Field, S. A. Scollen, C. Luccarini, C. Baynes, J. Morrison, A. M. Dunning, et al., Seq4SNPs: new software for retrieval of multiple, accurately annotated DNA sequences, ready formatted for SNP assay design, Bmc Bioinformatics, vol. 10, Jun 12 2009.
[42]P. Tiraboschi, L. A. Hansen, L. J. Thal, and J. Corey-Bloom, The importance of neuritic plaques and tangles to the development and evolution of AD, Neurology, vol. 62, pp. 1984-1989, Jun 8 2004.
[43]C. Bouras, P. R. Hof, P. Giannakopoulos, J. P. Michel, and J. H. Morrison, Regional Distribution of Neurofibrillary Tangles and Senile Plaques in the Cerebral-Cortex of Elderly Patients - a Quantitative-Evaluation of a One-Year Autopsy Population from a Geriatric Hospital, Cerebral Cortex, vol. 4, pp. 138-150, Mar-Apr 1994.
[44]M. Hashimoto, E. Rockenstein, L. Crews, and E. Masliah, Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases, Neuromolecular Medicine, vol. 4, pp. 21-35, 2003.
[45]I. Benilova, E. Karran, and B. De Strooper, The toxic A beta oligomer and Alzheimer's disease: an emperor in need of clothes, Nature Neuroscience, vol. 15, pp. 349-357, Mar 2012.
[46]P. R. Turner, K. O'Connor, W. P. Tate, and W. C. Abraham, Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory, Progress in Neurobiology, vol. 70, pp. 1-32, May 2003.
[47]C. Priller, T. Bauer, G. Mitteregger, B. Krebs, H. A. Kretzschmar, and J. Herms, Synapse formation and function is modulated by the amyloid precursor protein, Journal of Neuroscience, vol. 26, pp. 7212-7221, Jul 5 2006.
[48]T. Wisniewski, J. Ghiso, and B. Frangione, Biology of A beta amyloid in Alzheimer's disease, Neurobiology of Disease, vol. 4, pp. 313-328, 1997.
[49]H. Arai, S. Higuchi, T. Muramatsu, T. Iwatsubo, H. Sasaki, and J. Q. Trojanowski, Apolipoprotein E gene in diffuse Lewy body disease with or without co-existing Alzheimer's disease, Lancet, vol. 344, p. 1307, Nov 5 1994.
[50]D. J. Selkoe, Alzheimer's disease: genes, proteins, and therapy, Physiol Rev, vol. 81, pp. 741-66, Apr 2001.
[51]R. Cappai and A. R. White, Amyloid beta, International Journal of Biochemistry ＆ Cell Biology, vol. 31, pp. 885-889, Sep 1999.
[52]T. Saito, T. Suemoto, N. Brouwers, K. Sleegers, S. Funamoto, N. Mihira, et al., Potent amyloidogenicity and pathogenicity of Abeta43, Nat Neurosci, vol. 14, pp. 1023-32, Aug 2011.
[53]Y. Huang and L. Mucke, Alzheimer mechanisms and therapeutic strategies, Cell, vol. 148, pp. 1204-22, Mar 16 2012.
[54]B. Van Broeck, C. Van Broeckhoven, and S. Kumar-Singh, Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches, Neurodegener Dis, vol. 4, pp. 349-65, 2007.
[55]B. A. Yankner, L. K. Duffy, and D. A. Kirschner, Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides, Science, vol. 250, pp. 279-82, Oct 12 1990.
[56]X. Chen and S. D. Yan, Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer's disease, IUBMB Life, vol. 58, pp. 686-94, Dec 2006.
[57]N. H. Greig, M. P. Mattson, T. Perry, S. L. Chan, T. Giordano, K. Sambamurti, et al., New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists, Ann N Y Acad Sci, vol. 1035, pp. 290-315, Dec 2004.
[58]J. Hardy and D. J. Selkoe, The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics, Science, vol. 297, pp. 353-6, Jul 19 2002.
[59]J. Hardy and D. Allsop, Amyloid deposition as the central event in the aetiology of Alzheimer's disease, Trends Pharmacol Sci, vol. 12, pp. 383-8, Oct 1991.
[60]D. Schenk, R. Barbour, W. Dunn, G. Gordon, H. Grajeda, T. Guido, et al., Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse, Nature, vol. 400, pp. 173-7, Jul 8 1999.
[61]C. Haass, Initiation and propagation of neurodegeneration, Nat Med, vol. 16, pp. 1201-4, Nov 2010.
[62]E. Masliah, E. Rockenstein, I. Veinbergs, Y. Sagara, M. Mallory, M. Hashimoto, et al., beta-Amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease, Proceedings of the National Academy of Sciences of the United States of America, vol. 98, pp. 12245-12250, Oct 9 2001.
[63]P. Kurosinski, M. Guggisberg, and J. Gotz, Alzheimer's and Parkinson's disease - overlapping or synergistic pathologies?, Trends in Molecular Medicine, vol. 8, pp. 3-5, Jan 2002.
[64]D. K. Lahiri, M. R. Farlow, K. Sambamurti, N. H. Greig, E. Giacobini, and L. S. Schneider, A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease, Current Drug Targets, vol. 4, pp. 97-112, Feb 2003.
[65]H. F. Dovey, V. John, J. P. Anderson, L. Z. Chen, P. D. Andrieu, L. Y. Fang, et al., Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain, Journal of Neurochemistry, vol. 76, pp. 173-181, Jan 2001.
[66]C. Soto, E. M. Sigurdsson, L. Morelli, R. A. Kumar, E. M. Castano, and B. Frangione, beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer's therapy, Nature Medicine, vol. 4, pp. 822-826, Jul 1998.
[67]B. Permanne, C. Adessi, G. P. Saborio, S. Fraga, M. J. Frossard, J. Van Dorpe, et al., Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a beta-sheet breaker peptide, Faseb Journal, vol. 16, pp. 860-+, Apr 2002.
[68]R. A. Cherny, C. S. Atwood, M. E. Xilinas, D. N. Gray, W. D. Jones, C. A. McLean, et al., Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice, Neuron, vol. 30, pp. 665-676, Jun 2001.
[69]R. A. Marr, E. Rockenstein, A. Mukherjee, M. S. Kindy, L. B. Hersh, F. H. Gage, et al., Neprilysin gene transfer reduces human amyloid pathology in transgenic mice, Journal of Neuroscience, vol. 23, pp. 1992-1996, Mar 15 2003.
[70]W. Farris, S. Mansourian, Y. Chang, L. Lindsley, E. A. Eckman, M. P. Frosch, et al., Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo, Proceedings of the National Academy of Sciences of the United States of America, vol. 100, pp. 4162-4167, Apr 1 2003.
[71]S. Weggen, J. L. Eriksen, P. Das, S. A. Sagi, R. Wang, C. U. Pietrzik, et al., A subset of NSAIDs lower amyloidogenic A beta 42 independently of cyclooxygenase activity, Nature, vol. 414, pp. 212-216, Nov 8 2001.
[72]F. Hernandez, F. Lim, J. J. Lucas, C. Perez-Martin, F. Moreno, and J. Avila, Transgenic mouse models with tau pathology to test therapeutic agents for Alzheimer's disease, Mini Rev Med Chem, vol. 2, pp. 51-8, Feb 2002.
[73]C. J. Phiel, C. A. Wilson, V. M. Lee, and P. S. Klein, GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides, Nature, vol. 423, pp. 435-9, May 22 2003.
[74]G. Li, A. Faibushevich, B. J. Turunen, S. O. Yoon, G. Georg, M. L. Michaelis, et al., Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons, J Neurochem, vol. 84, pp. 347-62, Jan 2003.
[75]J. Gotz, J. R. Streffer, D. David, A. Schild, F. Hoerndli, L. Pennanen, et al., Transgenic animal models of Alzheimer's disease and related disorders: histopathology, behavior and therapy, Mol Psychiatry, vol. 9, pp. 664-83, Jul 2004.
[76]T. L. Platt, V. L. Reeves, and M. P. Murphy, Transgenic models of Alzheimer's disease: Better utilization of existing models through viral transgenesis, Biochim Biophys Acta, vol. 1832, pp. 1437-48, Sep 2013.
[77]M. Sastre, J. Walter, and S. M. Gentleman, Interactions between APP secretases and inflammatory mediators, J Neuroinflammation, vol. 5, p. 25, 2008.
[78]M. E. Egan, M. Pearson, S. A. Weiner, V. Rajendran, D. Rubin, J. Glockner-Pagel, et al., Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects, Science, vol. 304, pp. 600-2, Apr 23 2004.
[79]S. Eggert, K. Paliga, P. Soba, G. Evin, C. L. Masters, A. Weidemann, et al., The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation, J Biol Chem, vol. 279, pp. 18146-56, Apr 30 2004.
[80]P. H. Reddy and M. F. Beal, Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease, Trends Mol Med, vol. 14, pp. 45-53, Feb 2008.
[81]C. Zhang, Natural Compounds That Modulate BACE1-processing of Amyloid-beta Precursor Protein in Alzheimer's Disease, Discovery Medicine, vol. 76, pp. 189-197, Sep 2012.
[82]L. C. Walker, H. Levine, 3rd, M. P. Mattson, and M. Jucker, Inducible proteopathies, Trends Neurosci, vol. 29, pp. 438-43, Aug 2006.
[83]M. Hoshi, M. Sato, S. Matsumoto, A. Noguchi, K. Yasutake, N. Yoshida, et al., Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3 beta, Proceedings of the National Academy of Sciences of the United States of America, vol. 100, pp. 6370-6375, May 27 2003.
[84]M. P. Lambert, A. K. Barlow, B. A. Chromy, C. Edwards, R. Freed, M. Liosatos, et al., Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins, Proc Natl Acad Sci U S A, vol. 95, pp. 6448-53, May 26 1998.
[85]K. A. DaSilva, J. E. Shaw, and J. McLaurin, Amyloid-beta fibrillogenesis: Structural insight and therapeutic intervention, Experimental Neurology, vol. 223, pp. 311-321, Jun 2010.
[86]M. Takami, Y. Nagashima, Y. Sano, S. Ishihara, M. Morishima-Kawashima, S. Funamoto, et al., gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment, J Neurosci, vol. 29, pp. 13042-52, Oct 14 2009.
[87]I. Benilova and B. De Strooper, An overlooked neurotoxic species in Alzheimer's disease, Nat Neurosci, vol. 14, pp. 949-50, Aug 2011.
[88]B. De Strooper, R. Vassar, and T. Golde, The secretases: enzymes with therapeutic potential in Alzheimer disease, Nat Rev Neurol, vol. 6, pp. 99-107, Feb 2010.
[89]J. Shen and R. J. Kelleher, 3rd, The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism, Proc Natl Acad Sci U S A, vol. 104, pp. 403-9, Jan 9 2007.
[90]M. Bentahir, O. Nyabi, J. Verhamme, A. Tolia, K. Horre, J. Wiltfang, et al., Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms, J Neurochem, vol. 96, pp. 732-42, Feb 2006.
[91]Y. Qi-Takahara, M. Morishima-Kawashima, Y. Tanimura, G. Dolios, N. Hirotani, Y. Horikoshi, et al., Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase, J Neurosci, vol. 25, pp. 436-45, Jan 12 2005.
[92]M. Shimojo, N. Sahara, T. Mizoroki, S. Funamoto, M. Morishima-Kawashima, T. Kudo, et al., Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in cell models and knock-in mouse brains: familial Alzheimer disease-linked mutation impairs gamma-site cleavage of amyloid precursor protein C-terminal fragment beta, J Biol Chem, vol. 283, pp. 16488-96, Jun 13 2008.
[93]J. T. Jarrett, E. P. Berger, and P. T. Lansbury, Jr., The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, vol. 32, pp. 4693-7, May 11 1993.
[94]G. Bitan, M. D. Kirkitadze, A. Lomakin, S. S. Vollers, G. B. Benedek, and D. B. Teplow, Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways, Proc Natl Acad Sci U S A, vol. 100, pp. 330-5, Jan 7 2003.
[95]T. Saito, T. Suemoto, N. Brouwers, K. Sleegers, S. Funamoto, N. Mihira, et al., Potent amyloidogenicity and pathogenicity of A beta 43, Nature Neuroscience, vol. 14, pp. 1023-U120, Aug 2011.
[96]K. Zou, J. J. Liu, A. Watanabe, S. Hiraga, S. Y. Liu, C. Tanabe, et al., A beta(43) Is the Earliest-Depositing A beta Species in APP Transgenic Mouse Brain and Is Converted to A beta(41) by Two Active Domains of ACE, American Journal of Pathology, vol. 182, pp. 2322-2331, Jun 2013.
[97]P. St George-Hyslop and G. Schmitt-Ulms, ALZHEIMER'S DISEASE Selectively tuning gamma-secretase, Nature, vol. 467, pp. 36-37, Sep 2 2010.
[98]I. Benilova and B. De Strooper, An overlooked neurotoxic species in Alzheimer's disease, Nature Neuroscience, vol. 14, pp. 949-950, Aug 2011.
[99]J. Shen and R. J. Kelleher, The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism, Proceedings of the National Academy of Sciences of the United States of America, vol. 104, pp. 403-409, Jan 9 2007.
[100]M. P. Lambert, A. K. Barlow, B. A. Chromy, C. Edwards, R. Freed, M. Liosatos, et al., Diffusible, nonfibrillar ligands derived from A beta(1-42) are potent central nervous system neurotoxins, Proceedings of the National Academy of Sciences of the United States of America, vol. 95, pp. 6448-6453, May 26 1998.
[101]J. D. Harper, S. S. Wong, C. M. Lieber, and P. T. Lansbury, Observation of metastable A beta amyloid protofibrils by atomic force microscopy, Chemistry ＆ Biology, vol. 4, pp. 119-125, Feb 1997.
[102]D. M. Walsh, A. Lomakin, G. B. Benedek, M. M. Condron, and D. B. Teplow, Amyloid beta-protein fibrillogenesis - Detection of a protofibrillar intermediate, Journal of Biological Chemistry, vol. 272, pp. 22364-22372, Aug 29 1997.
[103]J. Hardy, The amyloid hypothesis for Alzheimer's disease: a critical reappraisal, J Neurochem, vol. 110, pp. 1129-34, Aug 2009.
[104]J. Kim, L. Onstead, S. Randle, R. Price, L. Smithson, C. Zwizinski, et al., A beta 40 inhibits amyloid deposition in vivo, Journal of Neuroscience, vol. 27, pp. 627-633, Jan 17 2007.
[105]E. McGowan, F. Pickford, J. Kim, L. Onstead, J. Eriksen, C. Yu, et al., A beta 42 is essential for parenchymal and vascular amyloid deposition in mice, Neuron, vol. 47, pp. 191-199, Jul 21 2005.
[106]A. Jan, O. Gokce, R. Luthi-Carter, and H. A. Lashuel, The ratio of monomeric to aggregated forms of A beta 40 and A beta 42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity, Journal of Biological Chemistry, vol. 283, pp. 28176-28189, Oct 17 2008.
[107]K. Ono, M. M. Condron, and D. B. Teplow, Effects of the English (H6R) and Tottori (D7N) Familial Alzheimer Disease Mutations on Amyloid beta-Protein Assembly and Toxicity, Journal of Biological Chemistry, vol. 285, pp. 23184-23195, Jul 23 2010.
[108]L. Keller, H. Welander, H. H. Chiang, L. O. Tjernberg, I. Nennesmo, A. K. Wallin, et al., The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of A beta in different brain regions, European Journal of Human Genetics, vol. 18, pp. 1202-1208, Nov 2010.
[109]H. Welander, J. Franberg, C. Graff, E. Sundstrom, B. Winblad, and L. O. Tjernberg, A beta 43 is more frequent than A beta 40 in amyloid plaque cores from Alzheimer disease brains, Journal of Neurochemistry, vol. 110, pp. 697-706, Jul 2009.
[110]S. Parvathy, P. Davies, V. Haroutunian, D. P. Purohit, K. L. Davis, R. C. Mohs, et al., Correlation between A beta x-40-, A beta x-42-, and A beta x-43-containing amyloid plaques and cognitive decline, Archives of Neurology, vol. 58, pp. 2025-2032, Dec 2001.
[111]T. Iizuka, M. Shoji, Y. Harigaya, T. Kawarabayashi, M. Watanabe, M. Kanai, et al., Amyloid Beta-Protein Ending at Thr43 Is a Minor Component of Some Diffuse Plaques in the Alzheimers-Disease Brain, but Is Not Found in Cerebrovascular Amyloid, Brain Research, vol. 702, pp. 275-278, Dec 8 1995.
[112]D. Van Der Spoel, E. Lindahl, B. Hess, G. Groenhof, A. E. Mark, and H. J. Berendsen, GROMACS: fast, flexible, and free, J Comput Chem, vol. 26, pp. 1701-18, Dec 2005.
[113]L. Verlet, Computer Experiments on Classical Fluids .I. Thermodynamical Properties of Lennard-Jones Molecules, Physical Review, vol. 159, pp. 98-＆, 1967.
[114]M. Levitt, Dynamics of Proteins and Nucleic-Acids - Mccammon,Ja, Harvey,Sc, Nature, vol. 330, pp. 120-120, Nov 12 1987.
[115]J. A. Mccammon, B. R. Gelin, and M. Karplus, Dynamics of Folded Proteins, Nature, vol. 267, pp. 585-590, 1977.
[116]E. A. Volkov, Difference Method of Estimating Errors in Numerical Solutions T0 Boundary Value Problems for an Ordinary Differential Equation, Doklady Akademii Nauk Sssr, vol. 197, pp. 758-＆, 1971.
[117]M. Levitt, Molecular-Dynamics of Native Protein .1. Computer-Simulation of Trajectories, Journal of Molecular Biology, vol. 168, pp. 595-620, 1983.
[118]M. Levitt, Molecular-Dynamics of Native Protein .2. Analysis and Nature of Motion, Journal of Molecular Biology, vol. 168, pp. 621-657, 1983.
[119]D. Beeman, Some Multistep Methods for Use in Molecular-Dynamics Calculations, Journal of Computational Physics, vol. 20, pp. 130-139, 1976.
[120]S. D. M. White, Numerical Recipes - the Art of Scientific Computing - Presse,Wh, Flannery,Bp, Teukolsky,Sa, Vetterling,Wt, Scientist, vol. 1, pp. 23-23, Nov 17 1986.
[121]M. Canales and J. A. Padro, Computer-Simulation Study of Relative Diffusion in Simple Liquids, Journal of Physics-Condensed Matter, vol. 3, pp. 7945-7955, Oct 7 1991.
[122]J. A. Cognet, J. Gabarro-Arpa, P. Cuniasse, G. V. Fazakerley, and M. Le Bret, Molecular mechanics and dynamics of an abasic frameshift in DNA and comparison to NMR data, J Biomol Struct Dyn, vol. 7, pp. 1095-115, Apr 1990.
[123]Y. Li and G. Wahnstrom, Molecular-dynamics simulation of hydrogen diffusion in palladium, Phys Rev B Condens Matter, vol. 46, pp. 14528-14542, Dec 1 1992.
[124]D. R. Flower, K. Phadwal, I. K. Macdonald, P. V. Coveney, M. N. Davies, and S. Wan, T-cell epitope prediction and immune complex simulation using molecular dynamics: state of the art and persisting challenges, Immunome Res, vol. 6 Suppl 2, p. S4, 2010.
[125]E. Lindahl, B. Hess, and D. van der Spoel, GROMACS 3.0: a package for molecular simulation and trajectory analysis, Journal of Molecular Modeling, vol. 7, pp. 306-317, 2001.
[126]W. R. P. Scott, P. H. Hunenberger, I. G. Tironi, A. E. Mark, S. R. Billeter, J. Fennen, et al., The GROMOS biomolecular simulation program package, Journal of Physical Chemistry A, vol. 103, pp. 3596-3607, May 13 1999.
[127]M. W. van der Kamp and V. Daggett, Influence of pH on the human prion protein: insights into the early steps of misfolding, Biophys J, vol. 99, pp. 2289-98, Oct 6 2010.
[128]Y. Ueda, H. Taketomi, and N. Go, Studies on Protein Folding, Unfolding, and Fluctuations by Computer-Simulation .2. 3-Dimensional Lattice Model of Lysozyme, Biopolymers, vol. 17, pp. 1531-1548, 1978.
[129]M. L. Klein and W. Shinoda, Large-scale molecular dynamics simulations of self-assembling systems, Science, vol. 321, pp. 798-800, Aug 8 2008.
[130]S. J. Marrink, A. H. de Vries, and A. E. Mark, Coarse grained model for semiquantitative lipid simulations, Journal of Physical Chemistry B, vol. 108, pp. 750-760, Jan 15 2004.
[131]S. J. Marrink, H. J. Risselada, S. Yefimov, D. P. Tieleman, and A. H. de Vries, The MARTINI force field: Coarse grained model for biomolecular simulations, Journal of Physical Chemistry B, vol. 111, pp. 7812-7824, Jul 12 2007.
[132]C. A. Lopez, A. J. Rzepiela, A. H. de Vries, L. Dijkhuizen, P. H. Hunenberger, and S. J. Marrink, Martini Coarse-Grained Force Field: Extension to Carbohydrates, Journal of Chemical Theory and Computation, vol. 5, pp. 3195-3210, Dec 2009.
[133]M. Venturoli, B. Smit, and M. M. Sperotto, Simulation studies of protein-induced bilayer deformations, and lipid-induced protein tilting, on a mesoscopic model for lipid bilayers with embedded proteins, Biophysical Journal, vol. 88, pp. 1778-1798, Mar 2005.
[134]L. Monticelli, S. K. Kandasamy, X. Periole, R. G. Larson, D. P. Tieleman, and S. J. Marrink, The MARTINI coarse-grained force field: Extension to proteins, Journal of Chemical Theory and Computation, vol. 4, pp. 819-834, May 2008.
[135]J. Gu, F. Bai, H. Li, and X. Wang, A generic force field for protein coarse-grained molecular dynamics simulation, Int J Mol Sci, vol. 13, pp. 14451-69, 2012.
[136]F. Massi and J. E. Straub, Energy landscape theory for Alzheimer's amyloid beta-peptide fibril elongation, Proteins, vol. 42, pp. 217-29, Feb 1 2001.
[137]R. Fildes and K. Nikolopoulos, Spyros Makridakis: An interview with the International Journal of Forecasting, International Journal of Forecasting, vol. 22, pp. 625-636, 2006.
[138]F. Massi, J. W. Peng, J. P. Lee, and J. E. Straub, Simulation study of the structure and dynamics of the Alzheimer's amyloid peptide congener in solution, Biophys J, vol. 80, pp. 31-44, Jan 2001.
[139]L. Shen, H. F. Ji, and H. Y. Zhang, Why Is the C-terminus of Abeta(1-42) more unfolded than that of Abeta(1-40)? Clues from hydrophobic interaction, J Phys Chem B, vol. 112, pp. 3164-7, Mar 13 2008.