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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
ORIGINAL ARTICLE

Abstract

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.

Keywords

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

Notes

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)

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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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