New Mechanism of Amyloid Fibril Formation

Author(s): Oxana Galzitskaya*.

Journal Name: Current Protein & Peptide Science

Volume 20 , Issue 6 , 2019

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Graphical Abstract:


Polymorphism is a specific feature of the amyloid structures. We have studied the amyloid structures and the process of their formation using the synthetic and recombinant preparations of Aβ peptides and their three fragments. The fibrils of different morphology were obtained for these peptides. We suppose that fibril formation by Aβ peptides and their fragments proceeds according to the simplified scheme: destabilized monomer → ring-like oligomer → mature fibril that consists of ringlike oligomers. We are the first who did 2D reconstruction of amyloid fibrils provided that just a ringlike oligomer is the main building block in fibril of any morphology, like a cell in an organism. Taking this into account it is easy to explain the polymorphism of fibrils as well as the splitting of mature fibrils under different external actions, the branching and inhomogeneity of fibril diameters. Identification of regions in the protein chains that form the backbone of amyloid fibril is a direction in the investigation of amyloid formation. It has been demonstrated for Aβ(1-42) peptide and its fragments that their complete structure is inaccessible for the action of proteases, which is an evidence of different ways of association of ring-like oligomers with the formation of fibrils. Based on the electron microscopy and mass spectrometry data, we have proposed a molecular model of the fibril formed by both Aβ peptide and its fragments. In connection with this, the unified way of formation of fibrils by oligomers, which we have discovered, could facilitate the development of relevant fields of medicine of common action.

Keywords: Oligomer, nucleus, polymorphism, fibril, amyloidogenic regions, isoform.

Virchow, R. Ueber eine im gehirn und ruckenmark des menschen aufgefunde substanz mit der chemishen reaction der cellulose. Virchows Arch. Path. Anat, 1854, 6, 135-138.
Astbury, W.T.; Dickinson, S.; Bailey, K. The X-ray interpretation of denaturation and the structure of the seed globulins. Biochem. J., 1935, 29, 2351-2360.
Eanes, E.D.; Glenner, G.G. X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. Off. J. Histochem. Soc., 1968, 16, 673-677.
Cohen, A.S.; Calkins, E. Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature, 1959, 183, 1202-1203.
Benditt, E.P.; Eriksen, N. Amyloid. 3. A protein related to the subunit structure of human amyloid fibrils. Proc. Natl. Acad. Sci. USA, 1966, 55, 308-316.
Shirahama, T.; Cohen, A.S. High-resolution electron microscopic analysis of the amyloid fibril. J. Cell Biol., 1967, 33, 679-708.
Glenner, G.G.; Terry, W.; Harada, M.; Isersky, C.; Page, D. Amyloid fibril proteins: Proof of homology with immunoglobulin light chains by sequence analyses. Science, 1971, 172, 1150-1151.
Benditt, E.P.; Eriksen, N.; Hermodson, M.A.; Ericsson, L.H. The major proteins of human and monkey amyloid substance: Common properties including unusual N-terminal amino acid sequences. FEBS Lett., 1971, 19, 169-173.
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., 1984, 120, 885-890.
Chiti, F.; Dobson, C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem., 2006, 75, 333-366.
Kayed, R.; Head, E.; Thompson, J.L.; McIntire, T.M.; Milton, S.C.; Cotman, C.W.; Glabe, C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science, 2003, 300, 486-489.
Kayed, R.; Lasagna-Reeves, C.A. Molecular mechanisms of amyloid oligomers toxicity. J. Alzheimers Dis., 2013, 33(Suppl. 1), S67-S78.
Fu, L.; Sun, Y.; Guo, Y.; Chen, Y.; Yu, B.; Zhang, H.; Wu, J.; Yu, X.; Kong, W.; Wu, H. Comparison of neurotoxicity of different aggregated forms of Aβ40, Aβ42 and Aβ43 in cell cultures. J. Pept. Sci. Off. Publ. Eur. Pept. Soc., 2017, 23, 245-251.
Garbuzynskiy, S.O.; Lobanov, M.Y.; Galzitskaya, O.V. FoldAmyloid: A method of prediction of amyloidogenic regions from protein sequence. Bioinformatics, 2010, 26, 326-332.
Selivanova, O.M.; Surin, A.K.; Ryzhykau, Y.L.; Glyakina, A.V.; Suvorina, M.Y.; Kuklin, A.I.; Rogachevsky, V.V.; Galzitskaya, O.V. To be fibrils or to be nanofilms? oligomers are building blocks for fibril and nanofilm formation of fragments of Aβ peptide. Langmuir ACS J. Surf. Colloids, 2018, 34, 2332-2343.
Selivanova, O.M.; Surin, A.K.; Marchenkov, V.V.; Dzhus, U.F.; Grigorashvili, E.I.; Suvorina, M.Y.; Glyakina, A.V.; Dovidchenko, N.V.; Galzitskaya, O.V. The mechanism underlying amyloid polymorphism is opened for Alzheimer’s disease amyloid-β peptide. J. Alzheimers Dis., 2016, 54, 821-830.
Markham, R.; Frey, S.; Hills, G.J. Methods for the enhancement of image detail and accentuation of structure in electron microscopy. Virology, 1963, 20, 88-102.
Inouye, H.; Fraser, P.E.; Kirschner, D.A. Structure of beta-crystallite assemblies formed by alzheimer beta-amyloid protein analogues: Analysis by X-ray diffraction. Biophys. J., 1993, 64, 502-519.
Malinchik, S.B.; Inouye, H.; Szumowski, K.E.; Kirschner, D.A. Structural analysis of Alzheimer’s beta(1-40) amyloid: Protofilament assembly of tubular fibrils. Biophys. J., 1998, 74, 537-545.
Surin, A.K.; Grigorashvili, E.I.; Suvorina, M.Y.; Selivanova, O.M.; Galzitskaya, O.V. Determination of regions involved in amyloid fibril formation for Aβ(1-40) peptide. Biochemistry (Mosc.), 2016, 81, 762-769.
Lashuel, H.A.; Hartley, D.M.; Petre, B.M.; Wall, J.S.; Simon, M.N.; Walz, T.; Lansbury, P.T. Mixtures of wild-type and a pathogenic (E22g) form of abeta40 in vitro accumulate protofibrils, including amyloid pores. J. Mol. Biol., 2003, 332, 795-808.
Bhak, G.; Lee, J-H.; Hahn, J-S.; Paik, S.R. Granular assembly of alpha-synuclein leading to the accelerated amyloid fibril formation with shear stress. PLoS One, 2009, 4, e4177.
Selivanova, O.M.; Glyakina, A.V.; Gorbunova, E.Y.; Mustaeva, L.G.; Suvorina, M.Y.; Grigorashvili, E.I.; Nikulin, A.D.; Dovidchenko, N.V.; Rekstina, V.V.; Kalebina, T.S.; Surin, A.K.; Galzitskaya, O.V. Structural model of amyloid fibrils for amyloidogenic peptide from bgl2p–glucantransferase of S. cerevisiae cell wall and its modifying analog. new morphology of amyloid fibrils. Biochim. Biophys. Acta, 2016, 1864, 1489-1499.
Selivanova, O.M.; Suvorina, M.Y.; Surin, A.K.; Dovidchenko, N.V.; Galzitskaya, O.V. Insulin and lispro insulin: What is common and different in their behavior? Curr. Protein Pept. Sci., 2017, 18, 57-64.
Goldsbury, C.; Frey, P.; Olivieri, V.; Aebi, U.; Müller, S.A. Multiple assembly pathways underlie amyloid-beta fibril polymorphisms. J. Mol. Biol., 2005, 352, 282-298.
Goldsbury, C.S.; Wirtz, S.; Müller, S.A.; Sunderji, S.; Wicki, P.; Aebi, U.; Frey, P. Studies on the in vitro assembly of A beta 1-40: implications for the search for a beta fibril formation inhibitors. J. Struct. Biol., 2000, 130, 217-231.
Perutz, M.F.; Finch, J.T.; Berriman, J.; Lesk, A. Amyloid fibers are water-filled nanotubes. Proc. Natl. Acad. Sci. USA, 2002, 99, 5591-5595.
Quist, A.; Doudevski, I.; Lin, H.; Azimova, R.; Ng, D.; Frangione, B.; Kagan, B.; Ghiso, J.; Lal, R. Amyloid ion channels: A common structural link for protein-misfolding disease. Proc. Natl. Acad. Sci. USA, 2005, 102, 10427-10432.
Makin, O.S.; Serpell, L.C. X-ray diffraction studies of amyloid structure. Methods Mol. Biol.Clifton NJ, 2005, 299, 67-80.
Sunde, M.; Serpell, L.C.; Bartlam, M.; Fraser, P.E.; Pepys, M.B.; Blake, C.C. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J. Mol. Biol., 1997, 273, 729-739.
Galzitskaya, O.V.; Surin, A.K.; Glyakina, A.V.; Rogachevsky, V.V.; Selivanova, O.M. Should the treatment of amyloidosis be personified? Molecular mechanism of amyloid formation by Aβ peptide and its fragments. J. Alzheimers Dis. Rep., 2018, 2(1), 181-199.
Galzitskaya, O.V.; Selivanova, O.M. Rosetta stone for amyloid fibrils: The key role of ring-like oligomers in amyloidogenesis. J. Alzheimers Dis., 2017, 59, 785-795.
Lu, J-X.; Qiang, W.; Yau, W-M.; Schwieters, C.D.; Meredith, S.C.; Tycko, R. Molecular structure of β-amyloid fibrils in alzheimer’s disease brain tissue. Cell, 2013, 154, 1257-1268.
Dovidchenko, N.V.; Finkelstein, A.V.; Galzitskaya, O.V. How to Determine the size of folding nuclei of protofibrils from the concentration dependence of the rate and lag-time of aggregation. I. modeling the amyloid protofibril formation. J. Phys. Chem. B, 2014, 118, 1189-1197.
Dovidchenko, N.V.; Galzitskaya, O.V. Computational approaches to identification of aggregation sites and the mechanism of amyloid growth. Adv. Exp. Med. Biol., 2015, 855, 213-239.
Dovidchenko, N.V.; Glyakina, A.V.; Selivanova, O.M.; Grigorashvili, E.I.; Suvorina, M.Y.; Dzhus, U.F.; Mikhailina, A.O.; Shiliaev, N.G.; Marchenkov, V.V.; Surin, A.K.; Galzitskaya, O.V. One of the possible mechanisms of amyloid fibrils formation based on the sizes of primary and secondary folding nuclei of Aβ40 and Aβ42. J. Struct. Biol., 2016, 194, 404-414.
Cohen, S.I.A.; Linse, S.; Luheshi, L.M.; Hellstrand, E.; White, D.A.; Rajah, L.; Otzen, D.E.; Vendruscolo, M.; Dobson, C.M.; Knowles, T.P.J. Proliferation of amyloid-B42 aggregates occurs through a secondary nucleation mechanism. Proc. Natl. Acad. Sci. USA, 2013, 110, 9758-9763.
Meisl, G.; Yang, X.; Hellstrand, E.; Frohm, B.; Kirkegaard, J.B.; Cohen, S.I.A.; Dobson, C.M.; Linse, S.; Knowles, T.P.J. Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides. Proc. Natl. Acad. Sci. USA, 2014, 111, 9384-9389.
Janssen, J.C.; Beck, J.A.; Campbell, T.A.; Dickinson, A.; Fox, N.C.; Harvey, R.J.; Houlden, H.; Rossor, M.N.; Collinge, J. Early onset familial Alzheimer’s disease: Mutation frequency in 31 families. Neurology, 2003, 60, 235-239.
Ono, K.; Condron, M.M.; Teplow, D.B. Effects of the English (H6R) and Tottori (D7N) familial Alzheimer disease mutations on amyloid beta-protein assembly and toxicity. J. Biol. Chem., 2010, 285, 23186-23197.
Rossi, G.; Macchi, G.; Porro, M.; Giaccone, G.; Bugiani, M.; Scarpini, E.; Scarlato, G.; Molini, G.E.; Sasanelli, F.; Bugiani, O.; Tagliavini, F. Fatal familial insomnia: Genetic, neuropathologic, and biochemical study of a patient from a new Italian kindred. Neurology, 1998, 50, 688-692.
Miravalle, L.; Tokuda, T.; Chiarle, R.; Giaccone, G.; Bugiani, O.; Tagliavini, F.; Frangione, B.; Ghiso, J. Substitutions at codon 22 of Alzheimer’s Abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J. Biol. Chem., 2000, 275, 27110-27116.
Wakutani, Y.; Watanabe, K.; Adachi, Y.; Wada-Isoe, K.; Urakami, K.; Ninomiya, H.; Saido, T.C.; Hashimoto, T.; Iwatsubo, T.; Nakashima, K. Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry, 2004, 75, 1039-1042.
Tomiyama, T.; Nagata, T.; Shimada, H.; Teraoka, R.; Fukushima, A.; Kanemitsu, H.; Takuma, H.; Kuwano, R.; Imagawa, M.; Ataka, S.; Wada, Y.; Yoshioka, E.; Nishizaki, T.; Watanabe, Y.; Mori, H. A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann. Neurol., 2008, 63, 377-387.
Schütz, A.K.; Vagt, T.; Huber, M.; Ovchinnikova, O.Y.; Cadalbert, R.; Wall, J.; Güntert, P.; Böckmann, A.; Glockshuber, R.; Meier, B.H. Atomic-resolution three-dimensional structure of amyloid β fibrils bearing the Osaka mutation. Angew. Chem. Int. Ed. Engl., 2015, 54, 331-335.
Chen, W-T.; Hong, C-J.; Lin, Y-T.; Chang, W-H.; Huang, H-T.; Liao, J-Y.; Chang, Y-J.; Hsieh, Y-F.; Cheng, C-Y.; Liu, H-C.; Chen, Y-R.; Cheng, I.H. Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-Zinc/Copper assemblies. PLoS One, 2012, 7, e35807.
Grabowski, T.J.; Cho, H.S.; Vonsattel, J.P.; Rebeck, G.W.; Greenberg, S.M. Novel amyloid precursor protein mutation in an iowa family with dementia and severe cerebral amyloid angiopathy. Ann. Neurol., 2001, 49, 697-705.
Qiang, W.; Yau, W-M.; Luo, Y.; Mattson, M.P.; Tycko, R. Antiparallel β-sheet architecture in Iowa-mutant β-amyloid fibrils. Proc. Natl. Acad. Sci. USA, 2012, 109, 4443-4448.
Sgourakis, N.G.; Yau, W-M.; Qiang, W. Modeling an in-register, parallel “Iowa” Aβ fibril structure using solid-state NMR data from labeled samples with Rosetta. Structure Lond. Engl, 1993, 2015(23), 216-227.
Hendriks, L.; van Duijn, C.M.; Cras, P.; Cruts, M.; Van Hul, W.; van Harskamp, F.; Warren, A.; McInnis, M.G.; Antonarakis, S.E.; Martin, J.J. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat. Genet., 1992, 1, 218-221.
Huet, A.; Derreumaux, P. Impact of the mutation A21G (Flemish Variant) on Alzheimer’s beta-amyloid dimers by molecular dynamics simulations. Biophys. J., 2006, 91, 3829-3840.
Jonsson, T.; Atwal, J.K.; Steinberg, S.; Snaedal, J.; Jonsson, P.V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.; Maloney, J.; Hoyte, K.; Gustafson, A.; Liu, Y.; Lu, Y.; Bhangale, T.; Graham, R.R.; Huttenlocher, J.; Bjornsdottir, G.; Andreassen, O.A. Jönsson, E.G.; Palotie, A.; Behrens, T.W.; Magnusson, O.T.; Kong, A.; Thorsteinsdottir, U.; Watts, R.J.; Stefansson, K. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature, 2012, 488, 96-99.
Lin, T-W.; Chang, C-F.; Chang, Y-J.; Liao, Y-H.; Yu, H-M.; Chen, Y-R. Alzheimer’s amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity. PLoS One, 2017, 12, e0174561.
Nilsberth, C.; Westlind-Danielsson, A.; Eckman, C.B.; Condron, M.M.; Axelman, K.; Forsell, C.; Stenh, C.; Luthman, J.; Teplow, D.B.; Younkin, S.G.; Näslund, J.; Lannfelt, L. The “Arctic” APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat. Neurosci., 2001, 4, 887-893.
Di Fede, G.; Catania, M.; Morbin, M.; Rossi, G.; Suardi, S.; Mazzoleni, G.; Merlin, M.; Giovagnoli, A.R.; Prioni, S.; Erbetta, A.; Falcone, C.; Gobbi, M.; Colombo, L.; Bastone, A.; Beeg, M.; Manzoni, C.; Francescucci, B.; Spagnoli, A.; Cantù, L.; Del Favero, E.; Levy, E.; Salmona, M.; Tagliavini, F. A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science, 2009, 323, 1473-1477.
Messa, M.; Colombo, L.; del Favero, E.; Cantù, L.; Stoilova, T.; Cagnotto, A.; Rossi, A.; Morbin, M.; Di Fede, G.; Tagliavini, F.; Salmona, M. The peculiar role of the A2V mutation in amyloid-β (Aβ) 1-42 molecular assembly. J. Biol. Chem., 2014, 289, 24143-24152.
Levy, E.; Carman, M.D.; Fernandez-Madrid, I.J.; Power, M.D.; Lieberburg, I.; van Duinen, S.G.; Bots, G.T.; Luyendijk, W.; Frangione, B. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, dutch type. Science, 1990, 248, 1124-1126.
Bird, T.D. Alzheimer Disease Overview.In GeneReviews®;; M.P.; Ardinger, H.H.; Pagon, R.A.; Wallace, S.E.; Bean, L.J.; Stephens, K.; Amemiya, A.; Eds.; University of Washington, Seattle: Seattle (WA),. , 1993.
Beel, A.J.; Mobley, C.K.; Kim, H.J.; Tian, F.; Hadziselimovic, A.; Jap, B.; Prestegard, J.H.; Sanders, C.R. Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): Does APP function as a cholesterol sensor? Biochemistry, 2008, 47, 9428-9446.
Duce, J.A.; Tsatsanis, A.; Cater, M.A.; James, S.A.; Robb, E.; Wikhe, K.; Leong, S.L.; Perez, K.; Johanssen, T.; Greenough, M.A.; Cho, H-H.; Galatis, D.; Moir, R.D.; Masters, C.L.; McLean, C.; Tanzi, R.E.; Cappai, R.; Barnham, K.J.; Ciccotosto, G.D.; Rogers, J.T.; Bush, A.I. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell, 2010, 142, 857-867.
Soscia, S.J.; Kirby, J.E.; Washicosky, K.J.; Tucker, S.M.; Ingelsson, M.; Hyman, B.; Burton, M.A.; Goldstein, L.E.; Duong, S.; Tanzi, R.E.; Moir, R.D. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One, 2010, 5, e9505.
Chen, W.; Gamache, E.; Rosenman, D.J.; Xie, J.; Lopez, M.M.; Li, Y-M.; Wang, C. Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site. Nat. Commun., 2014, 5, 3037.
Ghidoni, R.; Albertini, V.; Squitti, R.; Paterlini, A.; Bruno, A.; Bernardini, S.; Cassetta, E.; Rossini, P.M.; Squitieri, F.; Benussi, L.; Binetti, G. Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides. J. Alzheimers Dis., 2009, 18, 295-303.
Muratore, C.R.; Rice, H.C.; Srikanth, P.; Callahan, D.G.; Shin, T.; Benjamin, L.N.P.; Walsh, D.M.; Selkoe, D.J.; Young-Pearse, T.L. The familial Alzheimer’s disease APPV717I mutation alters APP processing and tau expression in IPSC-derived neurons. Hum. Mol. Genet., 2014, 23, 3523-3536.
Eckman, C.B.; Mehta, N.D.; Crook, R.; Perez-tur, J.; Prihar, G.; Pfeiffer, E.; Graff-Radford, N.; Hinder, P.; Yager, D.; Zenk, B.; Refolo, L.M.; Prada, C.M.; Younkin, S.G.; Hutton, M.; Hardy, J. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A Beta 42(43). Hum. Mol. Genet., 1997, 6, 2087-2089.
De Jonghe, C.; Esselens, C.; Kumar-Singh, S.; Craessaerts, K.; Serneels, S.; Checler, F.; Annaert, W.; Van Broeckhoven, C.; De Strooper, B. Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect abeta secretion and APP C-terminal fragment stability. Hum. Mol. Genet., 2001, 10, 1665-1671.
Guardia-Laguarta, C.; Pera, M.; Clarimón, J.; Molinuevo, J.L.; Sánchez-Valle, R.; Lladó, A.; Coma, M.; Gómez-Isla, T.; Blesa, R.; Ferrer, I.; Lleó, A. Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation. J. Neuropathol. Exp. Neurol., 2010, 69, 53-59.

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Year: 2019
Page: [630 - 640]
Pages: 11
DOI: 10.2174/1389203720666190125160937
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