請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78921完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳韻如(Yun-Ru Ruby Chen) | |
| dc.contributor.author | Ting-Yu Chang | en |
| dc.contributor.author | 張婷宇 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:29:20Z | - |
| dc.date.available | 2023-08-24 | |
| dc.date.copyright | 2018-08-24 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-17 | |
| dc.identifier.citation | 1. Burns, A. and S. Iliffe, Alzheimer’s disease. British Medical Journal, 2009. 338.
2. Organization, W.H., Dementia fact sheet N°362. World Health Organization. 3. Stelzmann, R.A., H. Norman Schnitzlein, and F. Reed Murtagh, An English translation of Alzheimer's 1907 paper,“Über eine eigenartige Erkankung der Hirnrinde”. Clinical Anatomy: The Official Journal of the American Association of Clinical Anatomists and the British Association of Clinical Anatomists, 1995. 8(6): p. 429-431. 4. Association, A.s., 2018 Alzheimer's disease facts and figures. Alzheimer's & Dementia, 2018. 14(3): p. 367-429. 5. Brookmeyer, R., et al., Forecasting the global burden of Alzheimer’s disease. Alzheimer's & dementia, 2007. 3(3): p. 186-191. 6. Abbott, A., A problem for our age. Nature, 2011. 475(7355): p. S2. 7. Lindsay, J., et al., Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. American Journal of Epidemiology, 2002. 156(5): p. 445-453. 8. Tanzi, R.E. and L. Bertram, Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell, 2005. 120(4): p. 545-555. 9. Jellinger, K.A., Head injury and dementia. Current Opinion in Neurology, 2004. 17(6): p. 719-723. 10. Simons, M., et al., Cholesterol and Alzheimer’s disease Is there a link? Neurology, 2001. 57(6): p. 1089-1093. 11. Florent-Bechard, S., et al., The essential role of lipids in Alzheimer's disease. Biochimie, 2009. 91(6): p. 804-809. 12. van Echten-Deckert, G. and J. Walter, Sphingolipids: critical players in Alzheimer’s disease. Progress in Lipid Research, 2012. 51(4): p. 378-393. 13. Biessels, G. and L. Kappelle, Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? 2005, Portland Press Limited. 14. Hölscher, C., Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. 2011, Portland Press Limited. 15. Zatta, P., et al., Alzheimer's disease, metal ions and metal homeostatic therapy. Trends in Pharmacological Sciences, 2009. 30(7): p. 346-355. 16. Duce, J.A. and A.I. Bush, Biological metals and Alzheimer's disease: implications for therapeutics and diagnostics. Progress in Neurobiology, 2010. 92(1): p. 1-18. 17. Amadoruge, P.C. and K.J. Barnham, Alzheimer's disease and metals: a review of the involvement of cellular membrane receptors in metallosignalling. International Journal of Alzheimer’s Disease, 2011. 2011. 18. Roberts, B.R., et al., The role of metallobiology and amyloid‐β peptides in Alzheimer’s disease. Journal of Neurochemistry, 2012. 120: p. 149-166. 19. Green, R.C., et al., Risk of dementia among white and African American relatives of patients with Alzheimer disease. Jama, 2002. 287(3): p. 329-336. 20. Pinhel, M., et al., Genetic Variants Related to Lipid Metabolism as a Risk Factor for Late Onset Alzheimer's Disease in Brazilian Population (P05. 077). Neurology, 2012. 78(1 Supplement): p. P05. 077-P05. 077. 21. Heun, R., et al. Risks for primary progressive dementia and for depression in first-degree relatives of patients with Alzheimer's disease and geriatric depression. in American Journal of Medical Genetics. 1998. Wiley-Liss Div John Wiley & Sons Inc, 605 Third Ave, New York, NY 10158-0012 USA. 22. Lautenschlager, N., et al., Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old? Neurology, 1996. 46(3): p. 641-650. 23. Saunders, A.M., et al., Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease. Neurology, 1993. 43(8): p. 1467-1467. 24. Farrer, L.A., et al., Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. Jama, 1997. 278(16): p. 1349-1356. 25. Loy, C.T., et al., Genetics of dementia. The Lancet, 2014. 383(9919): p. 828-840. 26. Gottesman, R.F., et al., Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) cohort. Jama, 2017. 74(10): p. 1246-1254. 27. Solomon, A., et al., Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dementia and Geriatric Cognitive Disorders, 2009. 28(1): p. 75-80. 28. Meng, X.-F., et al., Midlife vascular risk factors and the risk of Alzheimer's disease: a systematic review and meta-analysis. Journal of Alzheimer's disease, 2014. 42(4): p. 1295-1310. 29. Fitzpatrick, A.L., et al., Incidence and prevalence of dementia in the Cardiovascular Health Study. Journal of the American Geriatrics Society, 2004. 52(2): p. 195-204. 30. Kukull, W.A., et al., Dementia and Alzheimer disease incidence: a prospective cohort study. Archives of Neurology, 2002. 59(11): p. 1737-1746. 31. Evans, D.A., et al., Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Archives of Neurology, 2003. 60(2): p. 185-189. 32. Yoo, S.W., et al., Corrigendum: a network flow-based analysis of cognitive reserve in normal ageing and Alzheimer’s disease. Scientific Reports, 2015. 5: p. 12125. 33. Yoo, S.W., et al., A network flow-based analysis of cognitive reserve in normal ageing and Alzheimer’s disease. Scientific Reports, 2015. 5: p. 10057. 34. Stern, Y., Cognitive reserve in ageing and Alzheimer's disease. The Lancet Neurology, 2012. 11(11): p. 1006-1012. 35. Wang, H.-X., W. Xu, and J.-J. Pei, Leisure activities, cognition and dementia. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2012. 1822(3): p. 482-491. 36. Saczynski, J.S., et al., The effect of social engagement on incident dementia: the Honolulu-Asia Aging Study. American Journal of Epidemiology, 2006. 163(5): p. 433-440. 37. Sajeev, G., et al., Late-life cognitive activity and dementia: a systematic review and bias analysis. Epidemiology (Cambridge, Mass.), 2016. 27(5): p. 732-742. 38. Henry, W., H. Querfurth, and F. LaFerla, Mechanisms of disease Alzheimer’s disease. The New England Journal of Medicine, 2010. 362: p. 329-44. 39. Cacace, R., K. Sleegers, and C. Van Broeckhoven, Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimer's & Dementia, 2016. 12(6): p. 733-748. 40. Cummings, J.L., T. Morstorf, and K. Zhong, Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer's Research & Therapy, 2014. 6(4): p. 37. 41. Lemere, C.A. and E. Masliah, Can Alzheimer disease be prevented by amyloid-β immunotherapy? Nature Reviews Neurology, 2010. 6(2): p. 108. 42. Delrieu, J., et al., ‘Clinical trials in Alzheimer’s disease’: immunotherapy approaches. Journal of Neurochemistry: REVIEW, 2012. 120: p. 186-193. 43. Ritchie, C.W., et al., Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Archives of Neurology, 2003. 60(12): p. 1685-1691. 44. Bush, A.I., Drug development based on the metals hypothesis of Alzheimer's disease. Journal of Alzheimer's disease, 2008. 15(2): p. 223-240. 45. Bulic, B., et al., Development of tau aggregation inhibitors for Alzheimer's disease. Angewandte Chemie International Edition, 2009. 48(10): p. 1740-1752. 46. Gauthier, S., et al., Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. The Lancet, 2016. 388(10062): p. 2873-2884. 47. Wischik, C.M., et al., Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. Journal of Alzheimer's Disease, 2015. 44(2): p. 705-720. 48. Sunde, M., et al., Common core structure of amyloid fibrils by synchrotron X-ray diffraction1. Journal of Molecular Biology, 1997. 273(3): p. 729-739. 49. Klunk, W.E., R.F. Jacob, and R.P. Mason, Quantifying amyloid β-peptide (Aβ) aggregation using the Congo Red-Aβ (CR–Aβ) spectrophotometric assay. Analytical Biochemistry, 1999. 266(1): p. 66-76. 50. Naiki, H., et al., Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavine T. Analytical Biochemistry, 1989. 177(2): p. 244-249. 51. Tycko, R. and R.B. Wickner, Molecular structures of amyloid and prion fibrils: consensus versus controversy. Accounts of Chemical Research, 2013. 46(7): p. 1487-1496. 52. Hardy, J. and D. Allsop, Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends in Pharmacological Sciences, 1991. 12: p. 383-388. 53. Kang, J., et al., The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature, 1987. 325(6106): p. 733. 54. Thinakaran, G. and E.H. Koo, Amyloid precursor protein trafficking, processing, and function. Journal of Biological Chemistry, 2008. 283(44): p. 29615-29619. 55. Vingtdeux, V., N. Sergeant, and L. Buée, Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Frontiers in Physiology, 2012. 3: p. 229. 56. Francis, R., et al., aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Developmental Cell, 2002. 3(1): p. 85-97. 57. Bibl, M., et al., Blood‐based neurochemical diagnosis of vascular dementia: a pilot study. Journal of Neurochemistry, 2007. 103(2): p. 467-474. 58. Schoonenboom, N.S., et al., Amyloid β 38, 40, and 42 species in cerebrospinal fluid: more of the same? Annals of Neurology, 2005. 58(1): p. 139-142. 59. Burdick, D., et al., Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. Journal of Biological Chemistry, 1992. 267(1): p. 546-554. 60. Jarrett, J.T., 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, 1993. 32(18): p. 4693-4697. 61. Manna, M. and C. Mukhopadhyay, Binding, conformational transition and dimerization of amyloid-β peptide on GM1-containing ternary membrane: insights from molecular dynamics simulation. PloS one, 2013. 8(8): p. e71308. 62. Wilson, A.C., et al., TDP-43 in aging and Alzheimer's disease-a review. International Journal of Clinical and Experimental Pathology, 2011. 4(2): p. 147. 63. Wang, H.-Y., et al., Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics, 2004. 83(1): p. 130-139. 64. Buratti, E., et al., Nuclear factor TDP‐43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. The EMBO Journal, 2001. 20(7): p. 1774-1784. 65. Buratti, E. and F.E. Baralle, Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci, 2008. 13(867-7): p. 8. 66. Leino, M., S.N. Popova, and I. Alafuzoff, Transactive DNA binding protein 43 rather than other misfolded proteins in the brain is associated with islet amyloid polypeptide in pancreas in aged subjects with diabetes mellitus. Journal of Alzheimer's Disease, 2017. 59(1): p. 43-56. 67. Amador‐Ortiz, C., et al., TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Annals of Neurology, 2007. 61(5): p. 435-445. 68. Bigio, E.H., TAR DNA-binding protein-43 in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer disease. 2008, Springer. 69. Arai, T., et al., Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta neuropathologica, 2009. 117(2): p. 125-136. 70. Ayala, Y.M., et al., Human, Drosophila, and C. elegans TDP43: nucleic acid binding properties and splicing regulatory function. Journal of Molecular Biology, 2005. 348(3): p. 575-588. 71. Buratti, E. and F.E. Baralle, Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. Journal of Biological Chemistry, 2001. 72. Buratti, E., et al., TDP-43 binds HNRNP A/B through its C-terminal tail: An important region for the inhibition of CFTR Exon 9 splicing. Journal of Biological Chemistry, 2005. 73. Buratti, E. and F.E. Baralle, TDP-43: gumming up neurons through protein–protein and protein–RNA interactions. Trends in Biochemical Sciences, 2012. 37(6): p. 237-247. 74. Shiina, Y., et al., TDP-43 dimerizes in human cells in culture. Cellular and Molecular Neurobiology, 2010. 30(4): p. 641-652. 75. Kuo, P.-H., et al., Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Research, 2009. 37(6): p. 1799-1808. 76. Fang, Y.-S., et al., Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nature communications, 2014. 5: p. 4824. 77. Wang, Y.-T., et al., The truncated C-terminal RNA recognition motif of TDP-43 protein plays a key role in forming proteinaceous aggregates. Journal of Biological Chemistry, 2013. 288(13): p. 9049-9057. 78. Wang, I.-F., L.-S. Wu, and C.J. Shen, TDP-43: an emerging new player in neurodegenerative diseases. Trends in Molecular Medicine, 2008. 14(11): p. 479-485. 79. Neumann, M., et al., Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 2006. 314(5796): p. 130-133. 80. Neumann, M., et al., TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. Journal of Neuropathology & Experimental Neurology, 2007. 66(2): p. 152-157. 81. Sreedharan, J., et al., TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science, 2008. 319(5870): p. 1668-1672. 82. Johnson, B.S., et al., TDP-43 is intrinsically aggregation-prone and ALS-linked mutations accelerate aggregation and increase toxicity. Journal of Biological Chemistry, 2009: p. jbc. M109. 010264. 83. Arai, T., et al., TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochemical and Biophysical Research Communications, 2006. 351(3): p. 602-611. 84. Kwong, L.K., et al., TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta neuropathologica, 2007. 114(1): p. 63-70. 85. Josephs, K.A., et al., TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta neuropathologica, 2014. 127(6): p. 811-824. 86. Cohen, T.J., et al., An acetylation switch controls TDP-43 function and aggregation propensity. Nature communications, 2015. 6: p. 5845. 87. Garnier, C., et al., Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates. Scientific Reports, 2017. 7(1): p. 6812. 88. Paolicelli, R.C., et al., TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron, 2017. 95(2): p. 297-308. e6. 89. Mori, F., et al., Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta neuropathologica, 2008. 116(2): p. 193-203. 90. Xu, Y.-F., et al., Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. Journal of Neuroscience, 2010. 30(32): p. 10851-10859. 91. Xu, Y.-F., et al., Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Molecular neurodegeneration, 2011. 6(1): p. 73. 92. Braun, R.J., et al., Neurotoxic TDP-43 triggers mitochondrion-dependent programmed cell death in yeast. Journal of Biological Chemistry, 2011: p. jbc. M110. 194852. 93. Lu, J., et al., Mitochondrial dysfunction in human TDP-43 transfected NSC34 cell lines and the protective effect of dimethoxy curcumin. Brain Research Bulletin, 2012. 89(5-6): p. 185-190. 94. Wang, W., et al., The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Human Molecular Genetics, 2013. 22(23): p. 4706-4719. 95. Wang, W., et al., The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature Medicine, 2016. 22(8): p. 869. 96. Wang, W., et al., Motor-coordinative and cognitive dysfunction caused by mutant TDP-43 could be reversed by inhibiting its mitochondrial localization. Molecular Therapy, 2017. 25(1): p. 127-139. 97. Magrane, J., et al., Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Human Molecular Genetics, 2013. 23(6): p. 1413-1424. 98. Stribl, C., et al., Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43. Journal of Biological Chemistry, 2014: p. jbc. M113. 515940. 99. Izumikawa, K., et al., TDP-43 stabilises the processing intermediates of mitochondrial transcripts. Scientific Reports, 2017. 7(1): p. 7709. 100. Ruan, L., et al., Cytosolic proteostasis through importing of misfolded proteins into mitochondria. Nature, 2017. 543(7645): p. 443. 101. Woo, J.-A., et al., Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. Nature Communications, 2017. 8: p. 15558. 102. Gao, J., et al., Abnormalities of mitochondrial dynamics in neurodegenerative diseases. Antioxidants, 2017. 6(2): p. 25. 103. Uryu, K., et al., Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. Journal of Neuropathology & Experimental Neurology, 2008. 67(6): p. 555-564. 104. Higashi, S., et al., Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies. Brain Research, 2007. 1184: p. 284-294. 105. Gu, J., et al., Transactive response DNA-binding protein 43 (TDP-43) regulates alternative splicing of tau exon 10: implications for the pathogenesis of tauopathies. Journal of Biological Chemistry, 2017: p. jbc. M117. 783498. 106. Liao, Y.-H. and Y.-R. Chen, A novel method for expression and purification of authentic amyloid-β with and without 15N labels. Protein Expression and Purification, 2015. 113: p. 63-71. 107. Edelhoch, H., Spectroscopic determination of tryptophan and tyrosine in proteins. Biochemistry, 1967. 6(7): p. 1948-1954. 108. Chen, W.-T., et al., Distinct effects of Zn2+, Cu2+, Fe3+, and Al3+ on amyloid-β stability, oligomerization, and aggregation: amyloid-β destabilization promotes annular protofibril formation. Journal of Biological Chemistry, 2011: p. jbc. M110. 177246. 109. Ni, C.-L., et al., Folding stability of amyloid-β 40 monomer is an important determinant of the nucleation kinetics in fibrillization. The FASEB Journal, 2011. 25(4): p. 1390-1401. 110. Tobias, R. and S. Kumaraswamy, Biomolecular binding kinetics assays on the Octet platform. ForteBio Interact, 2013. 111. Caccamo, A., A. Magrí, and S. Oddo, Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to Aβ oligomers accumulation. Molecular neurodegeneration, 2010. 5(1): p. 51. 112. Davis, S.A., et al., TDP-43 expression influences amyloidβ plaque deposition and tau aggregation. Neurobiology of Disease, 2017. 103: p. 154-162. 113. O'Brien, R.J. and P.C. Wong, Amyloid precursor protein processing and Alzheimer's disease. Annual Review of Neuroscience, 2011. 34: p. 185-204. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78921 | - |
| dc.description.abstract | 阿茲海默症是一種慢性的神經退化性疾病，影響全球數千萬65歲以上的老年人口。根據類澱粉胜肽假說，乙型類澱粉胜肽的聚集對阿茲海默症發病機轉至關重要，而其中乙型類澱粉胜肽的寡聚體被認為是主要的毒性來源及致病形式。前類澱粉蛋白質被乙型分泌酶及丙型分泌酶切割後產生乙型類澱粉胜肽，以含有40個胺基酸及42個胺基酸的產物為大宗，了解乙型類澱粉胜肽將有助於促進阿茲海默症治療方法的進展。近年來有研究顯示，在阿茲海默症患者的腦中也發現了肌萎縮側索硬化症相關蛋白TDP-43的聚集，實驗室先前的研究亦顯示TDP-43的寡聚體會抑制乙型類澱粉胜肽的聚集，因此我們認為TDP-43在阿茲海默症的發病機制中可能扮演了重要的角色。在我們的研究中利用生化技術檢視了全長TDP-43對乙型類澱粉胜肽聚集過程的影響，發現其會減緩乙型類澱粉胜肽聚集，形成纖維的量也會減少，透過圓二色性光譜，我們也觀察到在全長TDP-43存在的情況下，乙型類澱粉胜肽停留在隨機螺旋(random coil)時間較長。為了瞭解TDP-43是如何抑制乙型類澱粉胜肽聚集，我們也製備數個較短的TDP-43蛋白，包含N端區域、與核糖核酸的結合區域及兩者合併。我們發現TDP-43的N端區域可能是抑制乙型類澱粉胜肽聚集的主要構造，但核糖核酸結合區域可能也有協助的功能。此外，我們透過酵素結合免疫吸附分析法和生物膜干涉技術測試了TDP-43和乙型類澱粉胜肽之間的相互作用。我們的發現更進一步了解TDP-43抑制乙型類澱粉胜肽聚集的機制，將有助於釐清TDP-43在阿茲海默症中所扮演的角色。 | zh_TW |
| dc.description.abstract | Alzheimer‘s disease (AD) is a chronic neurodegenerative disease that affects tens of million people over 65 years old. According to the amyloid cascade hypothesis, amyloid β (Aβ) aggregation is critical to AD pathogenesis and Aβ oligomers are the primary pathogenic form. Aβ is generated from amyloid precursor protein (APP) proteolytic digested by β-secretase and γ-secretase and has two major isoforms, Aβ40 and Aβ42. Understanding the process of Aβ aggregation is helpful to facilitate therapeutic development for AD. Recently, aggregation of amyotrophic-lateral-sclerosis related protein, TDP-43, is also found in brain of AD patients. Our previous study showed that the oligomeric form of TDP-43, prevent Aβ40 forming amyloid fibrils. In addition, TDP-43 oligomers exhibited neurotoxicity. The configuration and function of TDP-43 oligomers are different from the normal TDP-43. These results indicate that TDP-43 may also play an important role in AD pathogenesis. In this study, we monitored the conformational change of Aβ40 when TDP-43 oligomers are present. Besides, several TDP-43 truncated proteins including N-terminal region, RRM1/RRM2 region, and C-terminal truncation are prepared. We demonstrated that the recombinant full-length human TDP-43 effectively inhibits Aβ40 fibrillization process at the initial stage and oligomeric stage. N-terminal domain of TDP-43 is the dominant structural region to inhibit Aβ40 fibrillization. In the milder shaking condition, the recombinant full-length human TDP-43 also had impact on the inhibition of Aβ42 fibrillization. Additionally, we studied the effect of TDP-43 in Aβ aggregation and interaction by ELISA and biolayer interferometry analysis. Our results provided the detail of Aβ fibrillization affected by TDP-43. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:29:20Z (GMT). No. of bitstreams: 1 ntu-107-R05b22025-1.pdf: 3305413 bytes, checksum: ba38bfad31102638d3fdec7f2b84da7b (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii ABSTRACT iii CONTENTS iv LIST OF FIGURES vii LIST OF TABLES viii ABBREVIATIONS ix Chapter 1 Introduction 1 1.1 Alzheimer's disease 1 1.1.1 Overview 1 1.1.2 Risk factors and treatments 1 1.1.3 Hypotheses of the pathogenesis of Alzheimer’s disease 2 1.2 Amyloid-β 3 1.3 TDP-43 4 1.3.1 Overview 4 1.3.2 Structure of TDP-43 5 1.3.3 Aggregation and toxicity 5 1.3.4 The role of TDP-43 in AD 6 1.4 Aim 7 Chapter 2 Materials and methods 8 2.1 Materials 8 2.2 Methods 8 2.2.1 Protein expression and purification 8 2.2.2 Thioflavin T binding assay 11 2.2.3 Circular dichroism 12 2.2.4 Dot blotting 12 2.2.5 Transmission electron microscopy (TEM) 13 2.2.6 Gel filtration chromatography 13 2.2.7 Enzyme-linked immunoadsorbent assay (ELISA) 14 2.2.8 Biolayer interferometry analysis 14 2.2.9 Gel electrophoresis and western blot 15 2.2.10 Slot blotting 16 Chapter 3 Results 17 3.1 Materials prepartion 17 3.1.1 TDP-43 and its variants 17 3.1.2 Amyloid-β 19 3.2 TDP-43_FL retards Aβ40 fibrillization 21 3.2.1 ThT assay 22 3.2.2 Far-UV circular dichroism spectroscopy 22 3.2.3 Dot blot 23 3.3 TDP-43 variants also affect Aβ40 fibrillization 23 3.3.1 ThT assay 24 3.3.2 Western blot and Slot blot 25 3.3.3 TEM 25 3.4 TDP-43 variants interact with Aβ40 26 3.4.1 Enzyme-linked immunoadsorbent assay (ELISA) 26 3.4.2 Biolayer interferometry analysis 27 Chapter 4 Discussion 29 4.1 Aggregation process of Aβ in presence of TDP-43 29 4.2 Toxicity of Aβ and TDP-43 mixture 30 4.3 Technical improvement 31 4.3.1 Protein purification 31 4.3.2 Protein-protein interaction assay 31 FIGURE 32 TABLE 55 REFERENCE 59 | |
| dc.language.iso | en | |
| dc.subject | TDP-43 | zh_TW |
| dc.subject | 阿茲海默症 | zh_TW |
| dc.subject | 乙型類澱粉胜? | zh_TW |
| dc.subject | 蛋白質聚集 | zh_TW |
| dc.subject | 蛋白質交互作用 | zh_TW |
| dc.subject | protein interaction | en |
| dc.subject | amyloid-β | en |
| dc.subject | aggregation | en |
| dc.subject | TDP-43 | en |
| dc.title | 研究TDP-43對阿茲海默症中乙型類澱粉胜肽纖維化作用的影響 | zh_TW |
| dc.title | Investigation of TDP-43 effect on amyloid-β fibrillization in Alzheimer's disease | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王勝仕(Steven S.-S. Wang),廖憶純(Yi-Chun Liao),杜玲嫻(Ling-Hsien Tu) | |
| dc.subject.keyword | 阿茲海默症,乙型類澱粉胜?,蛋白質聚集,蛋白質交互作用,TDP-43, | zh_TW |
| dc.subject.keyword | amyloid-β,aggregation,protein interaction,TDP-43, | en |
| dc.relation.page | 64 | |
| dc.identifier.doi | 10.6342/NTU201803816 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-17 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| dc.date.embargo-lift | 2023-08-24 | - |
| 顯示於系所單位： | 生化科技學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-107-R05b22025-1.pdf 未授權公開取用 | 3.23 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。