Neurotoxicity Research

, Volume 35, Issue 2, pp 304–317 | Cite as

The Mode of Action of an Anti-Oligomeric Amyloid β-Protein Antibody Affects its Protective Efficacy

  • Yunlong Zhang
  • Yangyang Huai
  • Xiaoning Zhang
  • Chuli Song
  • Jing Cai
  • Yingjiu ZhangEmail author


The process of developing antibody drugs for Alzheimer’s disease therapy has been both long and difficult; however, recent advances suggest that antibodies against neurotoxic Αβ42 can suppress the progression of AD, especially on its early stage. Here, we obtained and characterized a novel anti-oligomeric Aβ42 aggregate scFv antibody, HT7, which could induce the significant disaggregation of Aβ42 aggregates through the release of stable and non-cytotoxic hexameric complexes that were composed of three scFv HT7s and one Aβ42 trimer, the latter being found to serve as the assembled subunit within larger Aβ42 aggregates in addition to existing freely between the cells. The docking model of the scFv HT7-Aβ42 complex revealed that only the N-terminal peptide of the Aβ42 molecule was bound into the groove between the VH and VL domains of scFv HT7. Thus, it was suggested that the hydrophobic interaction between the C-terminal peptides of Aβ42 molecules maintained the stability of the Aβ42 trimers or the Aβ42 trimer subunits. The saturation of Aβ42 trimer subunits by scFv HT7 and the subsequent dissociation of the scFv HT7-saturated Aβ42 trimer subunits from larger Aβ42 aggregates constituted the primary mechanisms underlying the high efficacy of scFv HT7. Our findings revealed that it was not sufficient for an anti-oligomeric Aβ42 antibody to exhibit high specificity and high affinity to the oligomeric Aβ42 aggregates in order to promote Aβ42 aggregate clearance and neutralize their cytotoxic effects. Here, for the first time, we proposed a “post-saturation dissociation” mechanism of Aβ42 oligomeric subunits for effective anti-Aβ42 antibodies.


scFv antibody Amyloid β-protein (Aβ) Subunit Aggregate Alzheimer’s disease 


Funding Information

This work was supported by two grants from the Jilin Province Science and Technology Department, China (20160204028YY, 20180101262JC).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12640_2018_9955_MOESM1_ESM.pdf (1.8 mb)
ESM 1 (PDF 1834 kb)


  1. Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S, Elliott JI, Van Nostrand WE, Smith SO (2010) Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils. Nat Struct Mol Biol 17:561–567CrossRefGoogle Scholar
  2. Antonios G, Borgers H, Richard BC, Brauss A, Meissner J, Weggen S, Pena V, Pillot T, Davies SL, Bakrania P, Matthews D, Brownlees J, Bouter Y, Bayer TA (2015) Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X. Sci Rep 5:17338CrossRefGoogle Scholar
  3. Balaban CL, Banchio C, Ceccarelli EA (2017) TAT-mediated transduction of bacterial redox proteins generates a cytoprotective effect on neuronal cells. PLoS One 12:e0184617CrossRefGoogle Scholar
  4. Cao H, Gao G, Gu Y, Zhang J, Zhang Y (2014) Trp358 is a key residue for the multiple catalytic activities of multifunctional amylase OPMA-N from Bacillus sp. ZW2531-1. Appl Microbiol Biotechnol 98:2101–2111CrossRefGoogle Scholar
  5. Chasseigneaux S, Allinquant B (2012) Functions of Abeta, sAPPalpha and sAPPbeta : similarities and differences. J Neurochem 120 Suppl 1:99–108CrossRefGoogle Scholar
  6. Colvin BA, Rogers VA, Kulas JA, Ridgway EA, Amtashar FS, Combs CK, Nichols MR (2017) The conformational epitope for a new Aβ42 protofibril-selective antibody partially overlaps with the peptide N-terminal region. J Neurochem 143(6):736–749CrossRefGoogle Scholar
  7. Copani A (2017) The underexplored question of beta-amyloid monomers. Eur J Pharmacol 817:71–75CrossRefGoogle Scholar
  8. Cui L, Huang X, Wang J, Zhang Y (2010) Specific and efficient anti-Abeta42 antibodies induced by sixteen tandem repeats of Abeta9. J Neuroimmunol 227:18–25CrossRefGoogle Scholar
  9. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R, Alzheimer’s Disease Cooperative Study Steering C, Solanezumab Study G (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370:311–321CrossRefGoogle Scholar
  10. Englund H, Sehlin D, Johansson AS, Nilsson LN, Gellerfors P, Paulie S, Lannfelt L, Pettersson FE (2010) Sensitive ELISA detection of amyloid-beta protofibrils in biological samples. J Neurochem 103:334–345Google Scholar
  11. Friguet B, Djavadi-Ohaniance L, Goldberg ME (1984) Some monoclonal antibodies raised with a native protein bind preferentially to the denatured antigen. Mol Immunol 21:673–677CrossRefGoogle Scholar
  12. Friguet B, Chaffotte AF, Djavadi-Ohaniance L, Goldberg ME (1985) Measurements of the true affinity constant in solution of antigen-antibody complexes by enzyme-linked immunosorbent assay. J Immunol Methods 77:305–319CrossRefGoogle Scholar
  13. Giuffrida ML, Tomasello MF, Pandini G, Caraci F, Battaglia G, Busceti C, Di Pietro P, Pappalardo G, Attanasio F, Chiechio S, Bagnoli S, Nacmias B, Sorbi S, Vigneri R, Rizzarelli E, Nicoletti F, Copani A (2015) Monomeric β-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons. Front Cell Neurosci 9:297CrossRefGoogle Scholar
  14. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E (2018) Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378:321–330CrossRefGoogle Scholar
  15. Huang X, Wang J, Cui L, Zou X, Zhang Y (2010) Recombinant GST-I-Aβ28-induced efficient serum antibody against Aβ42. J Neurosci Methods 186:52–59CrossRefGoogle Scholar
  16. Hunter S, Brayne C (2017) Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research? J Negat Results Biomed 16:1CrossRefGoogle Scholar
  17. Izuo N, Kasahara C, Murakami K, Kume T, Maeda M, Irie K, Yokote K, Shimizu T (2017) A toxic conformer of Aβ42 with a turn at 22-23 is a novel therapeutic target for Alzheimer’s disease. Sci Rep 7:11811CrossRefGoogle Scholar
  18. Ma B, Zhao J, Nussinov R (2016) Conformational selection in amyloid-based immunotherapy: survey of crystal structures of antibody-amyloid complexes. Biochim Biophys Acta 1860:2672–2681CrossRefGoogle Scholar
  19. Mroczko B, Groblewska M, Litman-Zawadzka A, Kornhuber J, Lewczuk P (2018) Amyloid β oligomers (AβOs) in Alzheimer’s disease. J Neural Transm (Vienna) 125:177–191CrossRefGoogle Scholar
  20. Murakami K (2014) Conformation-specific antibodies to target amyloid beta oligomers and their application to immunotherapy for Alzheimer’s disease. Biosci Biotechnol Biochem 78:1293–1305CrossRefGoogle Scholar
  21. Murakami K, Tokuda M, Suzuki T, Irie Y, Hanaki M, Izuo N, Monobe Y, Akagi K, Ishii R, Tatebe H, Tokuda T, Maeda M, Kume T, Shimizu T, Irie K (2016) Monoclonal antibody with conformational specificity for a toxic conformer of amyloid β42 and its application toward the Alzheimer’s disease diagnosis. Sci Rep 6:29038CrossRefGoogle Scholar
  22. Murray B, Sharma B, Belfort G (2017) N-terminal hypothesis for Alzheimer’s disease. ACS Chem Neurosci 8:432–434CrossRefGoogle Scholar
  23. Panza F, Seripa D, Solfrizzi V, Imbimbo BP, Lozupone M, Leo A, Sardone R, Gagliardi G, Lofano L, Creanza BC, Bisceglia P, Daniele A, Bellomo A, Greco A, Logroscino G (2016) Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients. Expert Opin Emerg Drugs 21:377–391CrossRefGoogle Scholar
  24. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR, Bapineuzumab 301 and 302 Clinical Trial Investigators (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370:322–333CrossRefGoogle Scholar
  25. Sebollela A et al (2017) A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-beta oligomers. J Neurochem 142:934–947Google Scholar
  26. Vandenberghe R et al (2016) Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther 8:18CrossRefGoogle Scholar
  27. Viola KL, Klein WL (2015) Amyloid beta oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 129:183–206CrossRefGoogle Scholar
  28. Vives E, Brodin P, Lebleu B (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272:16010–16017CrossRefGoogle Scholar
  29. Zhang Y, Chen X, Liu J, Zhang Y (2015a) The protective effects and underlying mechanism of an anti-oligomeric Aβ42 single-chain variable fragment antibody. Neuropharmacology 99:387–395CrossRefGoogle Scholar
  30. Zhang Y, Sun Y, Huai Y, Zhang YJ (2015b) Functional characteristics and molecular mechanism of a new scFv antibody against Aβ42 oligomers and immature protofibrils. Mol Neurobiol 52:1269–1281CrossRefGoogle Scholar
  31. Zhao J, Nussinov R, Ma B (2017) Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies. J Biol Chem 292:18325–18343CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication September/2018

Authors and Affiliations

  • Yunlong Zhang
    • 1
  • Yangyang Huai
    • 1
  • Xiaoning Zhang
    • 1
  • Chuli Song
    • 1
  • Jing Cai
    • 1
    • 3
  • Yingjiu Zhang
    • 1
    • 2
    Email author
  1. 1.Key Laboratory for Molecular Enzymology and Engineering of the Ministry of EducationJilin UniversityChangchunChina
  2. 2.School of Life ScienceJilin UniversityChangchunChina
  3. 3.China-Japan Union Hospital of Jilin UniversityChangchunChina

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