Computational Investigation of Gantenerumab and Crenezumab Recognition of Aβ Fibrils in Alzheimer's Disease Brain Tissue

Yujie Chen, Guanghong Wei, Jun Zhao, Ruth Nussinov, Buyong Ma

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapies using antibodies to lower assembled Aβ provide a promising approach and have been widely studied. Anti-amyloid antibodies are often selective to amyloid conformation, and the lack of amyloid-antibody structural information limits our understanding of these antibodies' conformation selection. Gantenerumab and crenezumab are two anti-Aβ antibodies that bind multiple forms of Aβ with different Aβ epitope preferences. Here, using molecular dynamic (MD) simulations, we study the binding of these two antibodies to the Aβ1-40 fibril, whose conformation is derived from an AD patient's brain tissue. We find that gantenerumab recognizes the Aβ1-11 monomer fragment only at slightly lower pH than the physiological environment where His6 of Aβ1-11 is protonated. Both gantenerumab and crenezumab bind with integrated Aβ fibril rather than binding to monomers within the fibril. Gantenerumab preferentially binds to the N-terminal region of the Aβ1-40 fibril, and the binding is driven by aromatic interactions. Crenezumab can recognize the N-terminal region, as well as the cross-section of the Aβ1-40 fibril, indicating its multiple binding modes in Aβ fibril recognition. These results demonstrate conformation-dependent interactions of antibody-amyloid recognition.

Original languageEnglish
Pages (from-to)3233-3244
Number of pages12
JournalACS Chemical Neuroscience
Volume11
Issue number20
DOIs
StatePublished - 21 Oct 2020

Keywords

  • Alzheimer's disease
  • Aβ amyloid
  • MD simulations
  • antibody
  • crenezumab
  • gantenerumab

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