Biochemistry (Moscow)

, Volume 83, Issue 9, pp 1057–1067 | Cite as

Anti-amyloid Therapy of Alzheimer’s Disease: Current State and Prospects

  • S. A. Kozin
  • E. P. Barykin
  • V. A. MitkevichEmail author
  • A. A. Makarov


Drug development for the treatment of Alzheimer’s disease (AD) has been for a long time focused on agents that were expected to support endogenous β-amyloid (Aβ) in a monomeric state and destroy soluble Aβ oligomers and insoluble Aβ aggregates. However, this strategy has failed over the last 20 years and was eventually abandoned. In this review, we propose a new approach to the anti-amyloid AD therapy based on the latest achievements in understanding molecular causes of cerebral amyloidosis in AD animal models.


Alzheimer’s disease amyloid-β isoaspartate zinc protein-protein complexes cerebral β-amyloidosis 



Alzheimer’s disease


disease-modifying agents



β-amyloid with isomerized Asp7 residue


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Alzheimer, A. (1906) Uber einen eigenartigen schweren Erkrankungsprozebeta der Hirnrinde, Neurol. Centralblatt, 23, 1129–1136.Google Scholar
  2. 2.
    Alzheimer’s Association (2014) 2014 Alzheimer’s disease facts and figures, Alzheimer’s Dementia, 10, e47–e92.Google Scholar
  3. 3.
    Gavrilova, S. I. (2007) Pharmacotherapy of Alzheimer’s Disease [in Russian], Pul’s, Moscow.Google Scholar
  4. 4.
    Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Piacentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., and St. George-Hyslop, P. H. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene, Nature, 376, 775–778.PubMedCrossRefGoogle Scholar
  5. 5.
    Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J. F., Bruni, A. C., Montesi, M. P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R. J., Wasco, W., Da Silva, H. A. R., Haines, J. L., Pericak-Vance, M. A., Tanzi, R. E., Roses, A. D., Fraser, P. E., Rommens, J. M., and St. George-Hyslop, P. H. (1995) Cloning of a gene bearing missense mutations in earlyonset familial Alzheimer’s disease, Nature, 375, 754–760.PubMedCrossRefGoogle Scholar
  6. 6.
    Querfurth, H. W., and LaFerla, F. M. (2010) Alzheimer’s disease, N. Engl. J. Med., 362, 329–344.PubMedCrossRefGoogle Scholar
  7. 7.
    Cummings, J. L. (2004) Alzheimer’s disease, N. Engl. J. Med., 351, 56–67.PubMedCrossRefGoogle Scholar
  8. 8.
    Cummings, J., Morstorf, T., and Zhong, K. (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures, Alzheimer’s Res. Ther., 6,37.CrossRefGoogle Scholar
  9. 9.
    Cummings, J., Lee, G., Mortsdorf, T., Ritter, A., and Zhong, K. (2017) Alzheimer’s disease drug development pipeline: 2017, Alzheimer’s Dement. (N.Y.), 3, 367–384.Google Scholar
  10. 10.
    Rygiel, K. (2016) Novel strategies for Alzheimer’s disease treatment: an overview of anti-amyloid beta monoclonal antibodies, Indian J. Pharmacol., 48, 629–636.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Guell-Bosch, J., Montoliu-Gaya, L., Esquerda-Canals, G., and Villegas, S. (2016) Abeta immunotherapy for Alzheimer’s disease: where are we? Neurodegen. Dis. Manag., 6, 179–181.CrossRefGoogle Scholar
  12. 12.
    Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O’Gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M. S., Quintero-Monzon, O., Scannevin, R. H., Arnold, H. M., Engber, T., Rhodes, K., Ferrero, J., Hang, Y., Mikulskis, A., Grimm, J., Hock, C., Nitsch, R. M., and Sandrock, A. (2016) The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease, Nature, 537, 50–56.PubMedCrossRefGoogle Scholar
  13. 13.
    Feinberg, H., Saldanha, J. W., Diep, L., Goel, A., Widom, A., Veldman, G. M., Weis, W. I., Schenk, D., and Basi, G. S. (2014) Crystal structure reveals conservation of amyloidbeta conformation recognized by 3D6 following humanization to bapineuzumab, Alzheimers Res. Ther., 6,31.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Leyhe, T., Andreasen, N., Simeoni, M., Reich, A., von Arnim, C. A., Tong, X., Yeo, A., Khan, S., Loercher, A., Chalker, M., Hottenstein, C., Zetterberg, H., Hilpert, J., and Mistry, P. (2014) Modulation of β-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: a phase I study, Alzheimer’s Res. Ther., 6,19.CrossRefGoogle Scholar
  15. 15.
    Zhao, J., Nussinov, R., and Ma, B. (2017) Mechanisms of recognition of amyloid-beta (Abeta) monomer, oligomer, and fibril by homologous antibodies, J. Biol. Chem., 292, 18325–18343.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Adolfsson, O., Pihlgren, M., Toni, N., Varisco, Y., Buccarello, A. L., Antoniello, K., Lohmann, S., Piorkowska, K., Gafner, V., Atwal, J. K., Maloney, J., Chen, M., Gogineni, A., Weimer, R. M., Mortensen, D. L., Friesenhahn, M., Ho, C., Paul, R., Pfeifer, A., Muhs, A., and Watts, R. J. (2012) An effector-reduced anti-betaamyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta, J. Neurosci., 32, 9677–9689.PubMedCrossRefGoogle Scholar
  17. 17.
    Ultsch, M., Li, B., Maurer, T., Mathieu, M., Adolfsson, O., Muhs, A., Pfeifer, A., Pihlgren, M., Bainbridge, T. W., Reichelt, M., Ernst, J. A., Eigenbrot, C., Fuh, G., Atwal, J. K., Watts, R. J., and Wang, W. (2016) Structure of crenezumab complex with Abeta shows loss of beta-hairpin, Sci. Rep., 6, 39374.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    La Porte, S. L., Bollini, S. S., Lanz, T. A., Abdiche, Y. N., Rusnak, A. S., Ho, W. H., Kobayashi, D., Harrabi, O., Pappas, D., Mina, E. W., Milici, A. J., Kawabe, T. T., Bales, K., Lin, J. C., and Pons, J. (2012) Structural basis of C-terminal beta-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer’s disease, J. Mol. Biol., 421, 525–536.PubMedCrossRefGoogle Scholar
  19. 19.
    Bohrmann, B., Baumann, K., Benz, J., Gerber, F., Huber, W., Knoflach, F., Messer, J., Oroszlan, K., Rauchenberger, R., Richter, W. F., Rothe, C., Urban, M., Bardroff, M., Winter, M., Nordstedt, C., and Loetscher, H. (2012) Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta, J. Alzheimer’s Dis., 28, 49–69.CrossRefGoogle Scholar
  20. 20.
    Crespi, G. A., Hermans, S. J., Parker, M. W., and Miles, L. A. (2015) Molecular basis for mid-region amyloid-beta capture by leading Alzheimer’s disease immunotherapies, Sci Rep., 5, 9649.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Gu, L., Liu, C., Stroud, J. C., Ngo, S., Jiang, L., and Guo, Z. (2014) Antiparallel triple-strand architecture for prefibrillar Abeta42 oligomers, J. Biol. Chem., 289, 27300–27313.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Paravastu, A. K., Leapman, R. D., Yau, W. M., and Tycko, R. (2008) Molecular structural basis for polymorphism in Alzheimer’s beta-amyloid fibrils, Proc. Natl. Acad. Sci. USA, 105, 18349–18354.PubMedCrossRefGoogle Scholar
  23. 23.
    Colvin, M. T., Silvers, R., Ni, Q. Z., Can, T. V., Sergeyev, I., Rosay, M., Donovan, K. J., Michael, B., Wall, J., Linse, S., and Griffin, R. G. (2016) Atomic resolution structure of monomorphic Aβ42 amyloid fibrils, J. Am. Chem. Soc., 138, 9663–9674.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tycko, R. (2016) Alzheimer’s disease: structure of aggregates revealed, Nature, 537, 492–493.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Walti, M. A., Ravotti, F., Arai, H., Glabe, C. G., Wall, J. S., Bockmann, A., Guntert, P., Meier, B. H., and Riek, R. (2016) Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril, Proc. Natl. Acad. Sci. USA, 113, E4976–E4984.PubMedCrossRefGoogle Scholar
  26. 26.
    Xiao, Y., Ma, B., McElheny, D., Parthasarathy, S., Long, F., Hoshi, M., Nussinov, R., and Ishii, Y. (2015) Abeta(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease, Nat. Struct. Mol. Biol., 22, 499–505.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Qi-Shi, D., Neng-Zhong, X., and Ri-Bo, H. (2015) Recent development of peptide drugs and advance on theory and methodology of peptide inhibitor design, Med. Chem., 11, 235–247.CrossRefGoogle Scholar
  28. 28.
    Cho, P. Y., Joshi, G., Johnson, J. A., and Murphy, R. M. (2014) Transthyretin-derived peptides as beta-amyloid inhibitors, ACS Chem. Neurosci., 5, 542–551.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Parthsarathy, V., McClean, P. L., Holscher, C., Taylor, M., Tinker, C., Jones, G., Kolosov, O., Salvati, E., Gregori, M., Masserini, M., and Allsop, D. (2013) A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1DeltaE9 mouse model of Alzheimer’s disease, PLoS One, 8, e54769.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Wang, Q., Liang, G., Zhang, M., Zhao, J., Patel, K., Yu, X., Zhao, C., Ding, B., Zhang, G., Zhou, F., and Zheng, J. (2014) De novo design of self-assembled hexapeptides as β-amyloid (Aβ) peptide inhibitors, ACS Chem. Neurosci., 5, 972–981.PubMedCrossRefGoogle Scholar
  31. 31.
    Gervais, F., Paquette, J., Morissette, C., Krzywkowski, P., Yu, M., Azzi, M., Lacombe, D., Kong, X., Aman, A., Laurin, J., Szarek, W. A., and Tremblay, P. (2007) Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis, Neurobiol. Aging, 28, 537–547.PubMedCrossRefGoogle Scholar
  32. 32.
    Giulian, D., Haverkamp, L. J., Yu, J., Karshin, W., Tom, D., Li, J., Kazanskaia, A., Kirkpatrick, J., and Roher, A. E. (1998) The HHQK domain of beta-amyloid provides a structural basis for the immunopathology of Alzheimer’s disease, J. Biol. Chem., 273, 29719–29726.PubMedCrossRefGoogle Scholar
  33. 33.
    Gauthier, S., Aisen, P. S., Ferris, S. H., Saumier, D., Duong, A., Haine, D., Garceau, D., Suhy, J., Oh, J., Lau, W., and Sampalis, J. (2009) Effect of tramiprosate in patients with mild-to-moderate Alzheimer’s disease: exploratory analyses of the MRI sub-group of the Alphase study, J. Nutr. Health Aging, 13, 550–557.PubMedCrossRefGoogle Scholar
  34. 34.
    Gauthier, S., Albert, M., Fox, N., Goedert, M., Kivipelto, M., Mestre-Ferrandiz, J., and Middleton, L. T. (2016) Why has therapy development for dementia failed in the last two decades? Alzheimer’s Dementia, 12, 60–64.PubMedCrossRefGoogle Scholar
  35. 35.
    Karran, E., Mercken, M., and De Strooper, B. (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics, Nat. Rev. Drug Discov., 10, 698–712.PubMedCrossRefGoogle Scholar
  36. 36.
    Schenk, D., Basi, G. S., and Pangalos, M. N. (2012) Treatment strategies targeting amyloid β-protein, Cold Spring Harb. Perspect. Med., 2, a006387.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Shankar, G., Li, S., Mehta, T., Garcia-Munoz, A., Shepardson, N., Smith, I., Brett, F., Farrell, M., Rowan, M., Lemere, C., Regan, C., Walsh, D., Sabatini, B., and Selkoe, D. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory, Nat. Med., 14, 837–842.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Villemagne, V. L., Perez, K. A., Pike, K. E., Kok, W. M., Rowe, C. C., White, A. R., Bourgeat, P., Salvado, O., Bedo, J., Hutton, C. A., Faux, N. G., Masters, C. L., and Barnham, K. J. (2010) Blood-borne amyloid-β dimer correlates with clinical markers of Alzheimer’s disease, J. Neurosci., 30, 6315–6322.PubMedCrossRefGoogle Scholar
  39. 39.
    Friedlich, A. L., Lee, J.-Y., van Groen, T., Cherny, R. A., Volitakis, I., Cole, T. B., Palmiter, R. D., Koh, J.-Y., and Bush, A. I. (2004) Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer’s disease, J. Neurosci., 24, 3453–3459.PubMedCrossRefGoogle Scholar
  40. 40.
    Faller, P., and Hureau, C. (2009) Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-beta peptide, Dalton Trans., 7, 1080–1094.CrossRefGoogle Scholar
  41. 41.
    Kozin, S. A., Zirah, S., Rebuffat, S., Hui Bon Hoa, G., and Debey, P. (2001) Zinc binding to Alzheimer’s Aβ(1–16) peptide results in stable soluble complex, Biochem. Biophys. Res. Commun., 285, 959–964.PubMedCrossRefGoogle Scholar
  42. 42.
    Kozin, S. A., Mezentsev, Y. V., Kulikova, A. A., Indeykina, M. I., Golovin, A. V., Ivanov, A. S., Tsvetkov, P. O., and Makarov, A. A. (2011) Zinc-induced dimerization of the amyloid-β metal-binding domain 1–16 is mediated by residues 11–14, Mol. BioSyst., 7, 1053–1055.PubMedCrossRefGoogle Scholar
  43. 43.
    Miller, Y., Ma, B., and Nussinov, R. (2010) Zinc ions promote Alzheimer Abeta aggregation via population shift of polymorphic states, Proc. Natl. Acad. Sci. USA, 107, 9490–9495.PubMedCrossRefGoogle Scholar
  44. 44.
    Luhrs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Dobeli, H., Schubert, D., and Riek, R. (2005) 3D structure of Alzheimer’s amyloid-beta(1–42) fibrils, Proc. Natl. Acad. Sci. USA, 102, 17342–17347.PubMedCrossRefGoogle Scholar
  45. 45.
    Dulin, F., Leveille, F., Ortega, J. B., Mornon, J.-P., Buisson, A., Callebaut, I., and Colloc’h, N. (2008) p3 peptide, a truncated form of Aβ devoid of synaptotoxic effect, does not assemble into soluble oligomers, FEBS Lett., 582, 1865–1870.Google Scholar
  46. 46.
    Walsh, D., Klyubin, I., Fadeeva, J., Cullen, W., Anwyl, R., Wolfe, M., Rowan, M., and Selkoe, D. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo, Nature, 416, 535–539.PubMedCrossRefGoogle Scholar
  47. 47.
    Istrate, A. N., Tsvetkov, P. O., Mantsyzov, A. B., Kulikova, A. A., Kozin, S. A., Makarov, A. A., and Polshakov, V. I. (2012) NMR solution structure of rat Aβ(1–16): toward understanding the mechanism of rats’ resistance to Alzheimer’s disease, Biophys. J., 102, 136–143.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kozin, S. A., and Makarov, A. A. (2015) New biomarkers and pharmaceutical targets for diagnostics and therapy of Alzheimer’s disease (molecular determinants of zinc-dependent β-amyloid oligomerization), Zh. Nevrol. Psikhiatr. im. S. S. Korsakova, 115, 5–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Kulikova, A. A., Makarov, A. A., and Kozin, S. A. (2015) A role of zinc ions and structural β-amyloid polymorphism in Alzheimer’s disease onset, Mol. Biol. (Moscow), 49, 249–263.CrossRefGoogle Scholar
  50. 50.
    Barykin, E. P., Mitkevich, V. A., Kozin, S. A., and Makarov, A. A. (2017) Amyloid beta modification: a key to the sporadic Alzheimer’s disease? Front. Genet., 8,58.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Kozin, S. A., Mitkevich, V. A., and Makarov, A. A. (2016) Amyloid-β containing isoaspartate 7 as potential biomarker and drug target in Alzheimer’s disease, Mendeleev Commun., 26, 269–275.CrossRefGoogle Scholar
  52. 52.
    Kulikova, A. A., Cheglakov, I. B., Kukharsky, M. S., Ovchinnikov, R. K., Kozin, S. A., and Makarov, A. A. (2016) Intracerebral injection of metal-binding domain of Abeta comprising the isomerized Asp7 increases the amyloid burden in transgenic mice, Neurotox. Res., 29, 551–557.PubMedCrossRefGoogle Scholar
  53. 53.
    Mattson, M. P. (1995) Untangling the pathophysio-chemistry of [beta]-amyloid, Nat. Struct. Mol. Biol., 2, 926–928.CrossRefGoogle Scholar
  54. 54.
    Mattson, M. P. (2004) Pathways towards and away from Alzheimer’s disease, Nature, 430, 631–639.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Murray, B., Sharma, B., and Belfort, G. (2017) N-terminal hypothesis for Alzheimer’s disease, ACS Chem. Neurosci., 8, 432–434.PubMedCrossRefGoogle Scholar
  56. 56.
    Baker, H. F., Ridley, R. M., Duchen, L. W., Crow, T. J., and Bruton, C. J. (1994) Induction of beta (A4)-amyloid in primates by injection of Alzheimer’s disease brain homogenate. Comparison with transmission of spongiform encephalopathy, Mol. Neurobiol., 8, 25–39.PubMedCrossRefGoogle Scholar
  57. 57.
    Ridley, R. M., Baker, H. F., Windle, C. P., and Cummings, R. M. (2006) Very long term studies of the seeding of betaamyloidosis in primates, J. Neural. Transm., 113, 1243–1251.PubMedCrossRefGoogle Scholar
  58. 58.
    Langer, F., Eisele, Y. S., Fritschi, S. K., Staufenbiel, M., Walker, L. C., and Jucker, M. (2011) Soluble Abeta seeds are potent inducers of cerebral beta-amyloid deposition, J. Neurosci., 31, 14488–14495.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Morales, R., Duran-Aniotz, C., Castilla, J., Estrada, L. D., and Soto, C. (2012) De novo induction of amyloid-[beta] deposition in vivo, Mol. Psychiatry, 17, 1347–1353.PubMedCrossRefGoogle Scholar
  60. 60.
    Rosen, R. F., Fritz, J. J., Dooyema, J., Cintron, A. F., Hamaguchi, T., Lah, J. J., LeVine, H., 3rd, Jucker, M., and Walker, L. C. (2012) Exogenous seeding of cerebral betaamyloid deposition in betaAPP-transgenic rats, J. Neurochem., 120, 660–666.PubMedCrossRefGoogle Scholar
  61. 61.
    Watts, J. C., Giles, K., Grillo, S. K., Lemus, A., DeArmond, S. J., and Prusiner, S. B. (2011) Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 108, 2528–2533.PubMedCrossRefGoogle Scholar
  62. 62.
    Eisele, Y. S., Bolmont, T., Heikenwalder, M., Langer, F., Jacobson, L. H., Yan, Z. X., Roth, K., Aguzzi, A., Staufenbiel, M., Walker, L. C., and Jucker, M. (2009) Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation, Proc. Natl. Acad. Sci. USA, 106, 12926–12931.PubMedCrossRefGoogle Scholar
  63. 63.
    Eisele, Y. S., Obermuller, U., Heilbronner, G., Baumann, F., Kaeser, S. A., Wolburg, H., Walker, L. C., Staufenbiel, M., Heikenwalder, M., and Jucker, M. (2010) Peripherally applied Abeta-containing inoculates induce cerebral betaamyloidosis, Science, 330, 980–982.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A. L., Vigouret, J. M., Paganetti, P., Walsh, D. M., Mathews, P. M., Ghiso, J., Staufenbiel, M., Walker, L. C., and Jucker, M. (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host, Science, 313, 1781–1784.PubMedCrossRefGoogle Scholar
  65. 65.
    Stohr, J., Watts, J. C., Mensinger, Z. L., Oehler, A., Grillo, S. K., DeArmond, S. J., Prusiner, S. B., and Giles, K. (2012) Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions, Proc. Natl. Acad. Sci. USA, 109, 11025–11030.PubMedCrossRefGoogle Scholar
  66. 66.
    Kumar, S., Rezaei-Ghaleh, N., Terwel, D., Thal, D. R., Richard, M., Hoch, M., Mc Donald, J. M., Wullner, U., Glebov, K., Heneka, M. T., Walsh, D. M., Zweckstetter, M., and Walter, J. (2011) Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer’s disease, EMBO J., 30, 2255–2265.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Nussbaum, J. M., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., Tayler, K., Wiltgen, B., Hatami, A., Ronicke, R., Reymann, K., Hutter-Paier, B., Alexandru, A., Jagla, W., Graubner, S., Glabe, C. G., Demuth, H. U., and Bloom, G. S. (2012) Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta, Nature, 485, 651–655.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Tsvetkov, P. O., Popov, I. A., Nikolaev, E. N., Archakov, A. I., Makarov, A. A., and Kozin, S. A. (2008) Isomerization of the Asp7 residue results in zinc-induced oligomerization of Alzheimer’s disease amyloid β(1–16) peptide, Chembiochem, 9, 1564–1567.PubMedCrossRefGoogle Scholar
  69. 69.
    Indeykina, M. I., Popov, I. A., Kozin, S. A., Kononikhin, A. S., Kharybin, O. N., Tsvetkov, P. O., Makarov, A. A., and Nikolaev, E. N. (2011) Capabilities of MS for analytical quantitative determination of the ratio of alpha-and betaAsp7 isoforms of the amyloid-beta peptide in binary mixtures, Anal. Chem., 83, 3205–3210.PubMedCrossRefGoogle Scholar
  70. 70.
    Pekov, S., Indeykina, M., Popov, I., Kononikhin, A., Bocharov, K., Kozin, S. A., Makarov, A. A., and Nikolaev, E. (2017) Application of MALDI-TOF/TOF-MS for relative quantitation of α-and β-Asp7 isoforms of amyloid-β peptide, Eur. J. Mass Spectrom., 24, 141–144.CrossRefGoogle Scholar
  71. 71.
    Zakharova, N. V., Shornikova, A. Y., Bugrova, A. E., Baybakova, V. V., Indeykina, M. I., Kononikhin, A. S., Popov, I. A., Kechko, O. I., Makarov, A. A., and Nikolaev, E. N. (2017) Evaluation of plasma peptides extraction methods by high-resolution mass spectrometry, Eur. J. Mass Spectrom., 23, 209–212.CrossRefGoogle Scholar
  72. 72.
    Kostyukevich, Y., Kononikhin, A., Popov, I., Indeykina, M., Kozin, S. A., Makarov, A. A., and Nikolaev, E. (2015) Supermetallization of peptides and proteins during electro-spray ionization, J. Mass Spectrom., 50, 1079–1087.PubMedCrossRefGoogle Scholar
  73. 73.
    Mekmouche, Y., Coppel, Y., Hochgrafe, K., Guilloreau, L., Talmard, C., Mazarguil, H., and Faller, P. (2005) Characterization of the ZnII binding to the peptide amyloid-beta1–16 linked to Alzheimer’s disease, Chembiochem, 6, 1663–1671.PubMedCrossRefGoogle Scholar
  74. 74.
    Zirah, S., Rebuffat, S., Kozin, S. A., Debey, P., Fournier, F., Lesage, D., and Tabet, J.-C. (2003) Zinc binding properties of the amyloid fragment Aβ(1–16) studied by electro-spray-ionization mass spectrometry, Int. J. Mass Spectrom., 228, 999–1016.CrossRefGoogle Scholar
  75. 75.
    Zirah, S., Kozin, S. A., Mazur, A. K., Blond, A., Cheminant, M., Segalas-Milazzo, I., Debey, P., and Rebuffat, S. (2006) Structural changes of region 1–16 of the Alzheimer disease amyloid β-peptide upon zinc binding and in vitro aging, J. Biol. Chem., 281, 2151–2161.PubMedCrossRefGoogle Scholar
  76. 76.
    Tsvetkov, P. O., Kulikova, A. A., Golovin, A. V., Tkachev, Y. V., Archakov, A. I., Kozin, S. A., and Makarov, A. A. (2010) Minimal Zn(2+) binding site of amyloid-β, Biophys. J., 99, L84–L86.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kozin, S. A., Kulikova, A. A., Istrate, A. N., Tsvetkov, P. O., Zhokhov, S. S., Mezentsev, Y. V., Kechko, O. I., Ivanov, A. S., Polshakov, V. I., and Makarov, A. A. (2015) The English (H6R) familial Alzheimer’s disease mutation facilitates zinc-induced dimerization of the amyloid-β metal-binding domain, Metallomics, 7, 422–425.PubMedCrossRefGoogle Scholar
  78. 78.
    Kulikova, A. A., Tsvetkov, P. O., Indeykina, M. I., Popov, I. A., Zhokhov, S. S., Golovin, A. V., Polshakov, V. I., Kozin, S. A., Nudler, E., and Makarov, A. A. (2014) Phosphorylation of Ser8 promotes zinc-induced dimerization of the amyloid-β metal-binding domain, Mol. BioSyst., 10, 2590–2596.PubMedCrossRefGoogle Scholar
  79. 79.
    Liu, S.-T., Howlett, G., and Barrow, C. J. (1999) Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the Aβ peptide of Alzheimer’s disease, Biochemistry, 38, 9373–9378.PubMedCrossRefGoogle Scholar
  80. 80.
    Nisbet, R. M., Nuttall, S. D., Robert, R., Caine, J. M., Dolezal, O., Hattarki, M., Pearce, L. A., Davydova, N., Masters, C. L., Varghese, J. N., and Streltsov, V. A. (2013) Structural studies of the tethered N-terminus of the Alzheimer’s disease amyloid-β peptide, Proteins, 81, 1748–1758.PubMedCrossRefGoogle Scholar
  81. 81.
    Adzhubei, A. A., Anashkina, A. A., and Makarov, A. A. (2017) Left-handed polyproline-II helix revisited: proteins causing proteopathies, J. Biomol. Struct. Dyn., 35, 2701–2713.PubMedCrossRefGoogle Scholar
  82. 82.
    Adzhubei, A. A., Sternberg, M. J. E., and Makarov, A. A. (2013) Polyproline-II helix in proteins: structure and function, J. Mol. Biol., 425, 2100–2132.PubMedCrossRefGoogle Scholar
  83. 83.
    Istrate, A. N., Kozin, S. A., Zhokhov, S. S., Mantsyzov, A. B., Kechko, O. I., Pastore, A., Makarov, A. A., and Polshakov, V. I. (2016) Interplay of histidine residues of the Alzheimer’s disease Aβ peptide governs its Zn-induced oligomerization, Sci. Rep., 6, 21734.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Polshakov, V. I., Mantsyzov, A. B., Kozin, S. A., Adzhubei, A. A., Zhokhov, S. S., van Beek, W., Kulikova, A. A., Indeykina, M. I., Mitkevich, V. A., and Makarov, A. A. (2017) A binuclear zinc interaction fold discovered in the homodimer of Alzheimer’s amyloid-beta fragment with taiwanese mutation D7H, Angew. Chem. Int. Ed. Engl., 56, 11734–11739.PubMedCrossRefGoogle Scholar
  85. 85.
    Mezentsev, Y. V., Medvedev, A. E., Kechko, O. I., Makarov, A. A., Ivanov, A. S., Mantsyzov, A. B., and Kozin, S. A. (2016) Zinc-induced heterodimer formation between metal-binding domains of intact and naturally modified amyloid-beta species: implication to amyloid seeding in Alzheimer’s disease? J. Biomol. Struct. Dyn., 34, 2317–2326.PubMedCrossRefGoogle Scholar
  86. 86.
    Jucker, M., and Walker, L. C. (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases, Nature, 501, 45–51.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Hosoda, R., Saido, T. C., Otvos, L. J., Arai, T., Mann, D. M. A., Lee, V. M.-Y., Trojanowski, J. Q., and Iwatsubo, T. (1998) Quantification of modified amyloid [beta] peptides in Alzheimer disease and Down syndrome brains, J. Neuropathol. Exp. Neurol., 57, 1089–1095.PubMedCrossRefGoogle Scholar
  88. 88.
    Roher, A. E., Lowenson, J. D., Clarke, S., Wolkow, C., Wang, R., Cotter, R. J., Reardon, I. M., Zurcher-Neely, H. A., Heinrikson, R. L., Ball, M. J., and Greenberg, B. D. (1993) Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer’s disease, J. Biol. Chem., 268, 3072–3083.PubMedGoogle Scholar
  89. 89.
    Shimizu, T., Matsuoka, Y., and Shirasawa, T. (2005) Biological significance of isoaspartate and its repair system, Biol. Pharm. Bull., 28, 1590–1596.PubMedCrossRefGoogle Scholar
  90. 90.
    Jucker, M., and Walker, L. C. (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders, Ann. Neurol., 70, 532–540.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kozin, S. A., Cheglakov, I. B., Ovsepyan, A. A., Telegin, G. B., Tsvetkov, P. O., Lisitsa, A. V., and Makarov, A. A. (2013) Peripherally applied synthetic peptide isoAsp7-Aβ(1–42) triggers cerebral β-amyloidosis, Neurotox. Res., 24, 370–376.PubMedCrossRefGoogle Scholar
  92. 92.
    Borchelt, D. R., Ratovitski, T., van Lare, J., Lee, M. K., Gonzales, V., Jenkins, N. A., Copeland, N. G., Price, D. L., and Sisodia, S. S. (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins, Neuron, 19, 939–945.PubMedCrossRefGoogle Scholar
  93. 93.
    Garcia-Alloza, M., Robbins, E. M., Zhang-Nunes, S. X., Purcell, S. M., Betensky, R. A., Raju, S., Prada, C., Greenberg, S. M., Bacskai, B. J., and Frosch, M. P. (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease, Neurobiol. Dis., 24, 516–524.PubMedCrossRefGoogle Scholar
  94. 94.
    Mitkevich, V. A., Petrushanko, I. Y., Yegorov, Y. E., Simonenko, O. V., Vishnyakova, K. S., Kulikova, A. A., Tsvetkov, P. O., Makarov, A. A., and Kozin, S. A. (2013) Isomerization of Asp7 leads to increased toxic effect of amyloid-β42 on human neuronal cells, Cell Death Dis., 4, e939.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Yurinskaya, M. M., Mitkevich, V. A., Kozin, S. A., Evgen’ev, M. B., Makarov, A. A., and Vinokurov, M. G. (2015) HSP70 protects human neuroblastoma cells from apoptosis and oxidative stress induced by amyloid peptide isoAsp7-Abeta(1–42), Cell Death Dis., 6, e1977.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Moreth, J., Mavoungou, C., and Schindowski, K. (2013) Passive anti-amyloid immunotherapy in Alzheimer’s disease: what are the most promising targets? Immun. Ageing, 10,18.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Busche, M. A., Grienberger, C., Keskin, A. D., Song, B., Neumann, U., Staufenbiel, M., Forstl, H., and Konnerth, A. (2015) Decreased amyloid-beta and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models, Nat. Neurosci., 18, 1725–1727.PubMedCrossRefGoogle Scholar
  98. 98.
    Lawrence, J. L. M., Tong, M., Alfulaij, N., Sherrin, T., Contarino, M., White, M. M., Bellinger, F. P., Todorovic, C., and Nichols, R. A. (2014) Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment, J. Neurosci., 34, 14210–14218.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Mediannikov, O., and Morozov, A. (2014) Peptide compound useful for inhibiting amyloid plaque formation, France Patent 2,966,827 (PCT/FR2011/052477, WO2012056157A1, EP2632938A1, JP2013542217A, US20130252901A1, RU2013106757/04(010044), CA2808196A1).Google Scholar
  100. 100.
    Tsvetkov, P. O., Cheglakov, I. B., Ovsepyan, A. A., Mediannikov, O. Y., Morozov, A. O., Telegin, G. B., and Kozin, S. A. (2015) Peripherally applied synthetic tetrapeptides HAEE and RADD slow down the development of cerebral beta-amyloidosis in AbetaPP/PS1 transgenic mice, J. Alzheimer’s Dis., 46, 849–853.CrossRefGoogle Scholar
  101. 101.
    Aisen, P. S., Gauthier, S., Ferris, S. H., Saumier, D., Haine, D., Garceau, D., Duong, A., Suhy, J., Oh, J., Lau, W. C., and Sampalis, J. (2011) Tramiprosate in mild-to-moderate Alzheimer’s disease-a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase study), Arch. Med. Sci., 7, 102–111.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Jucker, M., and Walker, L. C. (2015) Neurodegeneration: amyloid-[beta] pathology induced in humans, Nature, 525, 193–194.PubMedCrossRefGoogle Scholar
  103. 103.
    Sacks, C. A., Avorn, J., and Kesselheim, A. S. (2017) The failure of solanezumab-how the FDA saved taxpayers billions, N. Engl. J. Med., 376, 1706–1708.PubMedCrossRefGoogle Scholar
  104. 104.
    Moro, M. L., Phillips, A. S., Gaimster, K., Paul, C., Mudher, A., Nicoll, J. A. R., and Boche, D. (2018) Pyroglutamate and isoaspartate modified amyloid-beta in ageing and Alzheimer’s disease, Acta Neuropathol. Commun., 6,3.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Bu, X. L., Xiang, Y., Jin, W. S., Wang, J., Shen, L. L., Huang, Z. L., Zhang, K., Liu, Y. H., Zeng, F., Liu, J. H., Sun, H. L., Zhuang, Z. Q., Chen, S. H., Yao, X. Q., Giunta, B., Shan, Y. C., Tan, J., Chen, X. W., Dong, Z. F., Zhou, H. D., Zhou, X. F., Song, W., and Wang, Y. J. (2017) Blood-derived amyloid-[beta] protein induces Alzheimer’s disease pathologies, Mol. Psychiatry, doi: 10.1038/mp.2017.204.Google Scholar
  106. 106.
    Frederickson, C. J., Koh, J.-Y., and Bush, A. I. (2005) The neurobiology of zinc in health and disease, Nat. Rev. Neurosci., 6, 449–462.PubMedCrossRefGoogle Scholar
  107. 107.
    Lauren, J. (2014) Cellular prion protein as a therapeutic target in Alzheimer’s disease, J. Alzheimer’s Dis., 38, 227–244.CrossRefGoogle Scholar
  108. 108.
    Lauren, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., and Strittmatter, S. M. (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers, Nature, 457, 1128–1132.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Parri, R. H., and Dineley, T. K. (2010) Nicotinic acetyl-choline receptor interaction with beta-amyloid: molecular, cellular, and physiological consequences, Curr. Alzheimer Res., 7, 27–39.PubMedCrossRefGoogle Scholar
  110. 110.
    Spevacek, A. R., Evans, E. G. B., Miller, J. L., Meyer, H. C., Pelton, J. G., and Millhauser, G. L. (2013) Zinc drives a tertiary fold in the prion protein with familial disease mutation sites at the interface, Structure, 21, 236–246.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Watt, N. T., Griffiths, H. H., and Hooper, N. M. (2013) Neuronal zinc regulation and the prion protein, Prion, 7, 203–208.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Watt, N. T., Griffiths, H. H., and Hooper, N. M. (2014) Lipid rafts: linking prion protein to zinc transport and amyloid-β toxicity in Alzheimer’s disease, Fron. Cell Dev. Biol., 2,41.Google Scholar
  113. 113.
    Zawisza, I., Rozga, M., and Bal, W. (2012) Affinity of copper and zinc ions to proteins and peptides related to neurodegenerative conditions (Aβ, APP, α-synuclein, PrP), Coord. Chem. Rev., 256, 2297–2307.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • S. A. Kozin
    • 1
  • E. P. Barykin
    • 1
  • V. A. Mitkevich
    • 1
    Email author
  • A. A. Makarov
    • 1
  1. 1.Engelhardt Institute of Molecular BiologyRussian Academy of SciencesMoscowRussia

Personalised recommendations