Protein Misfolding and Amyloid Formation in Alzheimer’s Disease


The information necessary for proteins to correctly fold into biologically active three dimensional (3D) structures is present in the amino acid sequence. The ways by which proteins fold still remain one of the unexplained mysteries in the field of protein biochemistry. Investigating the impact and consequences of protein misfolding can help decipher the molecular causes behind the complex amyloid diseases such as Alzheimer’s disease (AD) and Parkinson’s disease. Various participating molecular entities like amyloid beta (Aβ), tau protein, and non-beta sheets are facilitating the pathogenesis of Alzheimer’s disease. Understanding their structure as well as their mechanism of action is useful to decode the therapeutic treatment for these complex diseases.


Protein misfolding Amyloid formation Amyloid beta structure Amyloid fibrils Alzheimer’s disease Neurodegenerative disorders 


  1. Aguzzi A, Calella AM (2009) Prions: protein aggregation and infectious diseases. Physiol Rev 89(4):1105–1152PubMedCrossRefGoogle Scholar
  2. Antzutkin ON, Balbach JJ, Leapman RD, Rizzo NW, Reed J, Tycko R (2000) Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of beta-sheets in Alzheimer’s beta-amyloid fibrils. Proc Natl Acad Sci U S A 97(24):13045–13050PubMedCentralPubMedCrossRefGoogle Scholar
  3. Antzutkin ON, Leapman RD, Balbach JJ, Tycko R (2002) Supramolecular structural constraints on Alzheimer’s beta-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 41(51):15436–15450PubMedCrossRefGoogle Scholar
  4. Apetri MM, Maiti NC, Zagorski MG, Carey PR, Anderson VE (2006) Secondary structure of alpha-synuclein oligomers: characterization by raman and atomic force microscopy. J Mol Biol 355(1):63–71PubMedCrossRefGoogle Scholar
  5. Balbach JJ, Ishii Y, Antzutkin ON, Leapman RD, Rizzo NW, Dyda F, Reed J, Tycko R (2000) Amyloid fibril formation by A beta 16–22, a seven-residue fragment of the Alzheimer’s beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39(45):13748–13759PubMedCrossRefGoogle Scholar
  6. Balbach JJ, Petkova AT, Oyler NA, Antzutkin ON, Gordon DJ, Meredith SC, Tycko R (2002) Supramolecular structure in full-length Alzheimer’s beta-amyloid fibrils: evidence for a parallel beta-sheet organization from solid-state nuclear magnetic resonance. Biophys J 83(2):1205–1216PubMedCentralPubMedCrossRefGoogle Scholar
  7. Ballew RM, Sabelko J, Gruebele M (1996) Direct observation of fast protein folding: the initial collapse of apomyoglobin. Proc Natl Acad Sci U S A 93:5759–5764PubMedCentralPubMedCrossRefGoogle Scholar
  8. Baumketner A, Bernstein SL, Wyttenbach T, Bitan G, Teplow DB, Bowers MT, Shea JE (2006) Amyloid beta-protein monomer structure: a computational and experimental study. Protein Sci 15(3):420–428PubMedCentralPubMedCrossRefGoogle Scholar
  9. Bemporad F, Chiti F (2012) Protein misfolded oligomers: experimental approaches, mechanism of formation, and structure-toxicity relationships. Chem Biol 19(3):315–327PubMedCrossRefGoogle Scholar
  10. Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer C, Rosenberry TL, Lewis J, Hutton M, Janus C (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27(14):3650–3662PubMedCrossRefGoogle Scholar
  11. Berson JF, Harper DC, Tenza D, Raposo G, Marks MS (2001) Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Mol Biol Cell 12(11):3451–3464PubMedCentralPubMedCrossRefGoogle Scholar
  12. Berson JF, Theos AC, Harper DC, Tenza D, Raposo G, Marks MS (2003) Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis. J Cell Biol 161(3):521–533PubMedCentralPubMedCrossRefGoogle Scholar
  13. Bertini I, Gonnelli L, Luchinat C, Mao JF, Nesi A (2011) A new structural model of Aβ40 fibrils. J Am Chem Soc 133:16013–16022PubMedCrossRefGoogle Scholar
  14. Bertram L, Tanzi RE (2004) Alzheimer’s disease: one disorder, too many genes. Hum Mol Genet 13:135–141CrossRefGoogle Scholar
  15. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739(2):216–223PubMedCrossRefGoogle Scholar
  16. Bitan G, Fradinger EA, Spring SM, Teplow DB (2005) Neurotoxic protein oligomers—what you see is not always what you get. Amyloid 12:88–95PubMedCrossRefGoogle Scholar
  17. Braak H, Braak E (1991) Neuropathological staging of Alzheimer’s disease-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  18. Brito RM, Dubitzky W, Rodrigues JR (2004) Protein folding and unfolding simulations: a new challenge for data mining. OMICS 8(2):153–166PubMedCrossRefGoogle Scholar
  19. Bu Z, Shi Y, Callaway DJ, Tycko R (2007) Molecular alignment within beta-sheets in Abeta(14–23) fibrils: solid-state NMR experiments and theoretical predictions. Biophys J 92(2):594–602PubMedCentralPubMedCrossRefGoogle Scholar
  20. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M (2002) Inherent cytotoxicity of aggregates implies a common origin for protein misfolding diseases. Nature 416:507–511PubMedCrossRefGoogle Scholar
  21. Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92:351–366PubMedCrossRefGoogle Scholar
  22. Bullock AN, Fersht AR (2001) Rescuing the functions of mutant p53. Nat Rev Cancer 1:68–76PubMedCrossRefGoogle Scholar
  23. Bush AI (2003) The metallobiology of Alzheimer’s disease. Trends Neurosci 26(4):207–214PubMedCrossRefGoogle Scholar
  24. Carrell RW, Gooptu B (1998) Conformational changes and disease–serpins, prions and Alzheimer’s. Curr Opin Struct Biol 8(6):799–809PubMedCrossRefGoogle Scholar
  25. Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298PubMedCrossRefGoogle Scholar
  26. Celej MS, Sarroukh R, Goormaghtigh E, Fidelio GD, Ruysschaert JM, Raussens V (2012) Toxic prefibrillar α-synuclein amyloid oligomers adopt a distinctive antiparallel β-sheet structure. Biochem J 443(3):719–726PubMedCrossRefGoogle Scholar
  27. Cerf E, Sarroukh R, Tamamizu-Kato S, Breydo L, Derclaye S, Dufrêne YF, Narayanaswami V, Goormaghtigh E, Ruysschaert JM, Raussens V (2009) Antiparallel beta-sheet: a signature structure of the oligomeric amyloid beta-peptide. Biochem J 421(3):415–423PubMedCrossRefGoogle Scholar
  28. Chaney MO, Webster SD, Kuo YM, Roher AE (1998) Molecular modeling of the A beta 1–42 peptide from Alzheimer’s disease. Protein Eng 11:761–767PubMedCrossRefGoogle Scholar
  29. Chen CD, Huff ME, Matteson J, Page L, Phillips R, Kelly JW, Balch WE (2001) Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca(2+) stabilization. EMBO J 20(22):6277–6287PubMedCentralPubMedCrossRefGoogle Scholar
  30. Chen W, Liu X, Huang Y, Jiang Y, Zou Q, Lin C (2012) Improved method for predicting protein fold patterns with ensemble classifiers. Genet Mol Res 11(1):174–181PubMedCrossRefGoogle Scholar
  31. Chiti F, Stefani M, Taddei N, Ramponi G, Dobson CM (2003) Rationalization of mutational effects on protein aggregation rates. Nature 424:805–808PubMedCrossRefGoogle Scholar
  32. Churchyard A, Lees AJ (1997) The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson’s disease. Neurology 49:1570–1576PubMedCrossRefGoogle Scholar
  33. Conway KA, Harper JD, Lansbury PT (2000) Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 39(10):2552–2563PubMedCrossRefGoogle Scholar
  34. Cork LC, Powers RE, Selkoe DJ, Davies P, Geyer JJ, Price DL (1988/1989). Neurofibrillary tangles and senile plaques in aged bears. J Neuropathol Exp Neurol 47:629–641. Erratum in: J Neuropathol Exp Neurol 48(4):497Google Scholar
  35. Creighton TE (1990) Protein folding. Biochem J 270:1–16PubMedCentralPubMedCrossRefGoogle Scholar
  36. Dastmalchi K, Dorman HJD, Vuorela H, Hiltunen R (2007) Plants as potential sources for drug development against Alzheimer’s disease. Int J Biomed Pharm Sci 2:83–104Google Scholar
  37. Davidowitz EJ, Chatterjee I, Moe JG (2008) Targeting tau oligomers for therapeutic development for Alzheimer’s disease and tauopathies. Curr Top Biotechnol 4:47–64Google Scholar
  38. Ding F, Borreguero JM, Buldyrey SV, Stanley HE, Dokholyan NV (2003) Mechanism for the alpha-helix to beta-hairpin transition. Proteins 53(2):220–228PubMedCrossRefGoogle Scholar
  39. Dobson CM (1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24:329–332PubMedCrossRefGoogle Scholar
  40. Dobson CM (2001) The structural basis of protein folding and its links with human disease. Philos Trans R Soc Lond B 356:133–145CrossRefGoogle Scholar
  41. Dobson CM (2003) Protein folding and misfolding. Nature 426:18–25CrossRefGoogle Scholar
  42. Dobson CM, Evans PA, Radford SE (1994) Understanding how proteins fold: the lysozyme story so far. Trends Biochem Sci 19:31–37PubMedCrossRefGoogle Scholar
  43. Dobson CM, Šali A, Karplus M (1998) Protein folding: a perspective from theory and experiment. Angew Chem Int Ed 37:868–893CrossRefGoogle Scholar
  44. Drago D, Bolognin S, Zatta P (2008) Role of metal ions in the Aβ oligomerization in Alzheimer’s disease and in other neurological disorders. Curr Alzheimer Res 5(6):500–507PubMedCrossRefGoogle Scholar
  45. Duce JA, Bush AI, Adlard PA (2011) Role of amyloid-β-metal interactions in Alzheimer’s disease. Future Neurol 6(5):641–659CrossRefGoogle Scholar
  46. Eanes ED, Glenner GG (1968) X-ray diffraction studies on amyloid filaments. J Histochem Cytochem 16(11):673–677PubMedCrossRefGoogle Scholar
  47. Faller P, Hureau C, Berthoumieu O (2013) Role of metal ions in the self-assembly of the Alzheimer’s amyloid-β peptide. Inorg Chem 52(21):12193–12206PubMedCrossRefGoogle Scholar
  48. Fändrich M, Schmidt M, Grigorieff N (2011) Recent progress in understanding Alzheimer’s β-amyloid structures. Trends Biochem Sci 36(6):338–345PubMedCentralPubMedCrossRefGoogle Scholar
  49. Fowler DM, Koulov AV, Alory-Jost C, Marks MS, Balch WE, Kelly JW (2006) Functional amyloid formation within mammalian tissue. PLoS Biol 4(1):e6PubMedCentralPubMedCrossRefGoogle Scholar
  50. Gandy S (2005) The role of cerebral amyloid β accumulation in common forms of Alzheimer disease. J Clin Investig 115:1121–1129PubMedCentralPubMedGoogle Scholar
  51. George AR, Howlett DR (1999) Computationally derived structural models of the beta-amyloid found in Alzheimer’s disease plaques and the interaction with possible aggregation inhibitors. Biopolymers 50:733–741PubMedCrossRefGoogle Scholar
  52. Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890PubMedCrossRefGoogle Scholar
  53. Gómez-Ramos A, Díaz-Hernández M, Cuadros R, Hernández F, Avila J (2006) Extracellular tau is toxic to neuronal cells. FEBS Lett 580(20):4842–4850PubMedCrossRefGoogle Scholar
  54. Gómez-Ramos A, Díaz-Hernández M, Rubio A, Miras-Portugal MT, Avila J (2008) Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci 4:673–681CrossRefGoogle Scholar
  55. Gordon DJ, Balbach JJ, Tycko R, Meredith SC (2004) Increasing the amphiphilicity of an amyloidogenic peptide changes the beta-sheet structure in the fibrils from antiparallel to parallel. Biophys J 86:428–434PubMedCentralPubMedCrossRefGoogle Scholar
  56. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM (2013) Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154(1):103–117PubMedCrossRefGoogle Scholar
  57. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol 8:101–112PubMedCrossRefGoogle Scholar
  58. Hansen CG, Nichols BJ (2009) Molecular mechanisms of clathrin-independent endocytosis. J Cell Sci 122:1713–1721PubMedCentralPubMedCrossRefGoogle Scholar
  59. Hardesty B, Kramer G (2001) Folding of a nascent peptide on the ribosome. Prog Nucleic Acid Res Mol Biol 66:41–66PubMedCrossRefGoogle Scholar
  60. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRefGoogle Scholar
  61. Hartmann T, Bieger SC, Brühl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat Med 3(9):1016–1020PubMedCrossRefGoogle Scholar
  62. Hefti F, Goure WF, Jerecic J, Iverson KS, Walicke PA, Krafft GA (2013) The case for soluble Aβ oligomers as a drug target in Alzheimer’s disease. Trends Pharmacol Sci 4(5):261–266CrossRefGoogle Scholar
  63. Herva ME, Zibaee S, Fraser G, Barker RA, Goedert M, Spillantini MG (2014) Anti-amyloid compounds inhibit α-synuclein aggregation induced by protein misfolding cyclic amplification (PMCA). J Biol Chem 289(17):11897–11905PubMedCentralPubMedCrossRefGoogle Scholar
  64. Hong DP, Han S, Fink AL, Uversky VN (2011) Characterization of the non-fibrillar α-synuclein oligomers. Protein Pept Lett 18(3):230–240PubMedCrossRefGoogle Scholar
  65. Hoozemans JJM, Veerhuis RV, Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol 110:165–172PubMedCrossRefGoogle Scholar
  66. Horwich A (2002) Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions. J Clin Invest 110:1221–1232PubMedCentralPubMedCrossRefGoogle Scholar
  67. Huang KL, Lin KJ, Hsiao IT, Kuo HC, Hsu WC et al (2013) Regional amyloid deposition in amnestic mild cognitive impairment and Alzheimer’s disease evaluated by [18F] AV-45 positron emission tomography in Chinese population. PLoS ONE 8(3):e58974PubMedCentralPubMedCrossRefGoogle Scholar
  68. Iqbal K, Wisniewski HM, Grundke-Iqbal INGE, Korthals JK, Terry RD (1975) Chemical pathology of neurofibrils. Neurofibrillary tangles of Alzheimer’s presenile-senile dementia. J Histochem Cytochem 23:563–569PubMedCrossRefGoogle Scholar
  69. Jenner P, Olanow CW (1996) Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 47:161S–170SCrossRefGoogle Scholar
  70. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Müller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325(6106):733–736PubMedCrossRefGoogle Scholar
  71. Kayed R, Sokolov Y, Edmonds B, McIntire TM, Milton SC, Hall JE, Glabe CG (2004) Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279:46363–46366PubMedCrossRefGoogle Scholar
  72. Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI (2012) Trans-cellular propagation of Tau aggregation by fibrillar species. J Biol Chem 287(23):19440–19451PubMedCentralPubMedCrossRefGoogle Scholar
  73. Kim HY, Cho MK, Kumar A, Maier E, Siebenhaar C, Becker S, Fernandez CO, Lashuel HA, Benz R, Lange A, Zweckstetter M (2009) Structural properties of pore-forming oligomers of α-synuclein. J Am Chem Soc 131:17482–17489PubMedCrossRefGoogle Scholar
  74. Kirkitadze MD, Condron MM, Teplow DB (2001) Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J Mol Biol 312(5):1103–1119PubMedCrossRefGoogle Scholar
  75. Kirschner DA, Abraham C, Selkoe DJ (1986) X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. Proc Natl Acad Sci U S A 83(2):503–507PubMedCentralPubMedCrossRefGoogle Scholar
  76. Klein WL, Krafft GA, Finch CE (2001) Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 24(4):219–224PubMedCrossRefGoogle Scholar
  77. Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D (2012) Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis 2012:731526PubMedCentralPubMedGoogle Scholar
  78. Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A 83(11):4044–4048PubMedCentralPubMedCrossRefGoogle Scholar
  79. Ksiezak-Reding H, Wall JS (2005) Characterization of paired helical filaments by scanning transmission electron microscopy. Microsc Res Tech 67(3–4):126–140PubMedCrossRefGoogle Scholar
  80. Kuhla B, Haase C, Flach K, Lüth HJ, Arendt T, Münch G (2007) Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation. J Biol Chem 282(10):6984–6991PubMedCrossRefGoogle Scholar
  81. Kurnik M, Hedberg L, Danielsson J, Oliveberg M (2012) Folding without charges. Proc Natl Acad Sci U S A 109(15):5705–5710PubMedCentralPubMedCrossRefGoogle Scholar
  82. La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11:247–258PubMedCrossRefPubMedCentralGoogle Scholar
  83. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95(11):6448–6453PubMedCentralPubMedCrossRefGoogle Scholar
  84. Lansbury PT, Costa PR, Griffiths JM, Simon EJ, Auger M, Halverson KJ, Kocisko DA, Hendsch ZS, Ashburn TT, Spencer RG (1995) Structural model for the beta-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide. Nat Struct Biol 2(11):990–998PubMedCrossRefGoogle Scholar
  85. Lathia JD, Okun E, Tang SC, Griffioen K, Cheng A, Mughal MR, Laryea G, Selvaraj PK, Ffrench-Constant C, Magnus T, Arumugam TV, Mattson MP (2008) Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci 28(51):13978–13984PubMedCentralPubMedCrossRefGoogle Scholar
  86. Lazo ND, Downing DT (1998) Amyloid fibrils may be assembled from beta-helical protofibrils. Biochemistry 37:1731–1735PubMedCrossRefGoogle Scholar
  87. Li LP, Darden TA, Bartolotti L, Kominos D, Pedersen LG (1999) An atomic model for the pleated beta-sheet structure of A beta amyloid protofilaments. Biophys J 76:2871–2878PubMedCentralPubMedCrossRefGoogle Scholar
  88. Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13:385–392PubMedCrossRefGoogle Scholar
  89. Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R (2013) Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154(6):1257–1268PubMedCrossRefGoogle Scholar
  90. Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, Schubert D, Riek R (2005) 3D structure of Alzheimer’s amyloid-β(1–42) fibrils. PNAS 102(48):17342–17347PubMedCentralPubMedCrossRefGoogle Scholar
  91. Maeda S, Sahara N, Saito Y, Murayama S, Ikai A, Takashima A (2006) Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer’s disease. Neurosci Res 54(3):197–201PubMedCrossRefGoogle Scholar
  92. Marks MS, Seabra MC (2001) The melanosome: membrane dynamics in black and white. Nat Rev Mol Cell Biol 2(10):738–748PubMedCrossRefGoogle Scholar
  93. Martha A, Anda-Hernández D, Karla I, León LD, Mena R, Campos-Peña V, Meraz-Ríos MA (2012) Tau and amyloid-β conformational change to β -sheet structures as effectors in the development of Alzheimer’s disease, Neuroscience – dealing with frontiers. InTech, Rijeka. ISBN 978-953-51-0207-6Google Scholar
  94. McKoy AF, Chen J, Schupbach T, Hecht MH (2014) Structure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer’s peptide, Aβ42. Chem Biol Drug Des 84(5):505–512PubMedCentralPubMedCrossRefGoogle Scholar
  95. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313(5794):1781–1784PubMedCrossRefGoogle Scholar
  96. Mondragón-Rodríguez S, Basurto-Islas G, Binder LI, García-Sierra F (2009) Conformational changes and cleavage; are these responsible for the tau aggregation in Alzheimer’s disease? Future Neurol 4(1):39–53CrossRefGoogle Scholar
  97. Nilsson MR, Driscoll M, Raleigh DP (2002) Low levels of asparagine deamidation can have a dramatic effect on aggregation of amyloidogenic peptides: implications for the study of amyloid formation. Protein Sci 11:342–349PubMedCentralPubMedCrossRefGoogle Scholar
  98. Oda T, Wals P, Osterburg HH, Johnson SA, Pasinetti GM, Morgan TE, Rozovsky I, Stine WB, Snyder SW, Holzman TF (1995) Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1–42) and forms slowly sedimenting A beta complexes that cause oxidative stress. Exp Neurol 136(1):22–31PubMedCrossRefGoogle Scholar
  99. Pappu RV, Nussinov R (2009) Protein folding: lessons learned and new frontiers. Phys Biol 6:010301 (2pp)PubMedCrossRefGoogle Scholar
  100. Paravastu AK, Leapman RD, Yau W-M, Tycko R (2008) Molecular structural basis for polymorphism in Alzheimer’s β-amyloid fibrils. Proc Natl Acad Sci U S A 105(47):18349–18354PubMedCentralPubMedCrossRefGoogle Scholar
  101. Pascher T, Chesick JP, Winkler JR, Gray HB (1996) Protein folding triggered by electron transfer. Science 271:1558–1560PubMedCrossRefGoogle Scholar
  102. Pepys MB (2001) Pathogenesis, diagnosis and treatment of systemic amyloidosis. Philos Trans R Soc Lond B Biol Sci 356(1406):203–210; discussion 210–1PubMedCentralPubMedCrossRefGoogle Scholar
  103. Pereira C, Santos MS, Oliveira C (1998) Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. Neuroreport 9(8):1749–1755PubMedCrossRefGoogle Scholar
  104. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer’s-amyloid fibrils. Science 307:262–265PubMedCrossRefGoogle Scholar
  105. Petkova AT, Yau WM, Tycko R (2006) Experimental constraints on quaternary structure in Alzheimer’s -amyloid fibrils. Biochemistry 45:498–512PubMedCentralPubMedCrossRefGoogle Scholar
  106. Petrakis S, Raskó T, Russ J, Friedrich RP, Stroedicke M et al (2012) Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1. PLoS Genet 8(8):e1002897PubMedCentralPubMedCrossRefGoogle Scholar
  107. Prusiner SB (1992) Chemistry and biology of prions. Biochemistry 31:12277–12288PubMedCrossRefGoogle Scholar
  108. Radford SE, Dobson CM (1999) From computer simulations to human disease: emerging themes in protein folding. Cell 97:291–298PubMedCrossRefGoogle Scholar
  109. Rambaran RN, Serpell LC (2008) Amyloid fibrils: abnormal protein assembly. Prion 2(3):112–117PubMedCentralPubMedCrossRefGoogle Scholar
  110. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR (2009) Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol 11(2):219–225PubMedCentralPubMedCrossRefGoogle Scholar
  111. Reynaud E (2010) Protein misfolding and degenerative diseases. Nat Educ 3:28–34Google Scholar
  112. Sadqi M, Hernández F, Pan U, Pérez M, Schaeberle MD, Avila J, Muñoz V (2002) Alpha-helix structure in Alzheimer’s disease aggregates of tau-protein. Biochemistry 41(22):7150–7155PubMedCrossRefGoogle Scholar
  113. Santa-Maria I, Varghese M, Ksiezak-Reding H, Dzhun A, Wang J, Pasinetti GM (2012) Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes. J Biol Chem 287(24):20522–20533PubMedCentralPubMedCrossRefGoogle Scholar
  114. Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJW, McFarlane HT, Madsen AO, Riekel C, Eisenberg D (2007) Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447:453–457PubMedCrossRefGoogle Scholar
  115. Scholtzova H, Chianchiano P, Pan J, Sun Y, Goñi F, Mehta PD, Wisniewski T (2014) Amyloid β and Tau Alzheimer’s disease related pathology is reduced by Toll-like receptor 9 stimulation. Acta Neuropathol Commun 2:101PubMedCentralPubMedGoogle Scholar
  116. Schultz C, Dehghani F, Hubbard GB, Thal DR, Struckhoff G, Braak E, Braak H (2000) Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons. J Neuropathol Exp Neurol 59:39–52PubMedGoogle Scholar
  117. Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B (1997) Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci U S A 94:4113–4118PubMedCentralPubMedCrossRefGoogle Scholar
  118. Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT (2009) Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci 32:150–159PubMedCrossRefGoogle Scholar
  119. Stöhr J, Watts JC, Mensinger ZL et al (2012) Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions. Proc Natl Acad Sci U S A 109(27):11025–11030PubMedCentralPubMedCrossRefGoogle Scholar
  120. Strittmatter WJ, Roses AD (1996) Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci 19:53–77PubMedCrossRefGoogle Scholar
  121. Sunde M, Blake CCF (1997) The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv Protein Chem 50:123–159PubMedCrossRefGoogle Scholar
  122. Sunde M, Serpell LC, Bartlam M, Fraser PE, Pepys MB, Blake CC (1997) Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J Mol Biol 273(3):729–739PubMedCrossRefGoogle Scholar
  123. Tan SY, Pepys MB (1994) Amyloidosis. Histopathology 25:403–414PubMedCrossRefGoogle Scholar
  124. Taylor JP, Hardy J, Fischbeck KH (2002) Toxic proteins in neurodegenerative disease. Science 296:1991–1995PubMedCrossRefGoogle Scholar
  125. Tayubi IA, Shome S, Barukab OM (2014) In silico analysis of detrimental mutation in EPHB2 gene causing Alzheimer’s disease. BMC Genomics 15(Suppl 2):P46PubMedCentralCrossRefGoogle Scholar
  126. Thomas PJ, Qu BH, Pedersen PL (1995) Defective protein folding as a basis of human disease. Trends Biochem Sci 20:456–459PubMedCrossRefGoogle Scholar
  127. Tjernberg LO, Callaway DJE, Tjernberg A, Hahne S, Lilliehook C, Terenius L, Thyberg J, Nordstedt C (1999) A molecular model of Alzheimer amyloid beta-peptide fibril formation. J Biol Chem 274:12619–12625PubMedCrossRefGoogle Scholar
  128. Toyama BH, Weissman JS (2011) Amyloid structure: conformational diversity and consequences. Annu Rev Biochem 80:557–585PubMedCrossRefGoogle Scholar
  129. Trojanowski J, Goedert M, Iwatsubo T, Lee V (1998) Fatal attractions: abnormal protein aggregation and neuron death in Parkinson’s disease and Lewy body dementia. Cell Death Differ 5:832–837PubMedCrossRefGoogle Scholar
  130. Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Zoghbi HY (2005) The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 122:633–644PubMedCrossRefGoogle Scholar
  131. Tycko R (2013) β-amyloid fibril structures, in vitro and in vivo. In: Jucker M, Christen Y (eds) Proteopathic seeds and neurodegenerative diseases. Research and perspectives in Alzheimer’s disease. Springer, Berlin/Heidelberg, pp 19–31CrossRefGoogle Scholar
  132. van Rooijen BD, Claessens MM, Subramaniam V (2008) Membrane binding of oligomeric α-synuclein depends on bilayer charge and packing. FEBS Lett 582:3788–3792PubMedCrossRefGoogle Scholar
  133. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL (2013) Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group. Lancet Neurol 12(4):357–367PubMedCrossRefGoogle Scholar
  134. Volles MJ, Lee SJ, Rochet JC, Shtilerman MD, Ding TT, Kessler JC, Lansbury PT (2001) Vesicle permeabilization by protofibrillar alpha synuclein: implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 40:7812–7819PubMedCrossRefGoogle Scholar
  135. Wang J, Dickson DW, Trojanowski JQ, Lee VM (1999) The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging. Exp Neurol 158(2):328–337PubMedCrossRefGoogle Scholar
  136. Xu S, Brunden KR, Trojanowski JQ, Lee VM (2010) Characterization of tau fibrillization in vitro. Alzheimers Dement 6(2):110–117PubMedCentralPubMedCrossRefGoogle Scholar
  137. Yoon S, Welsh WJ (2004) Detecting hidden sequence propensity for amyloid fibril formation. Protein Sci 13(8):2149–2160PubMedCentralPubMedCrossRefGoogle Scholar
  138. Younkin SG (1995) Evidence that A beta 42 is the real culprit in Alzheimer’s disease. Ann Neurol 37(3):287–288PubMedCrossRefGoogle Scholar
  139. Yu X, Luo Y, Dinkel P, Zheng J, Wei G, Margittai M, Nussinov R, Ma B (2012) Cross-seeding and conformational selection between three- and four-repeat human Tau proteins. J Biol Chem 287(18):14950–14959PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2015

Authors and Affiliations

  • Iftikhar Aslam Tayubi
    • 1
  • Ahmad Firoz
    • 2
    • 3
  • Adeel Malik
    • 4
  1. 1.Faculty of Computing and Information TechnologyKing Abdulaziz UniversityRabighKingdom of Saudi Arabia
  2. 2.School of Chemistry and BiochemistryThapar UniversityPatialaIndia
  3. 3.Biomedical Informatics Center of ICMRPost Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
  4. 4.Perdana University Centre for Bioinformatics (PU-CBi), MARDI ComplexJalan MAEPS PerdanaSerdangMalaysia

Personalised recommendations