Mechanism of C-Terminal Fragments of Amyloid β-Protein as Aβ Inhibitors: Do C-Terminal Interactions Play a Key Role in Their Inhibitory Activity?

Xueyun Zheng, Chun Wu, Deyu Liu, Huiyuan Li, Gal Bitan, Joan Emma Shea, Michael T. Bowers

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Targeting the early oligomerization of amyloid β protein (Aβ) is a promising therapeutic strategy for Alzheimer's disease (AD). Recently, certain C-terminal fragments (CTFs) derived from Aβ42 were shown to be potent inhibitors of Aβ-induced toxicity. The shortest peptide studied, Aβ(39-42), has been shown to modulate Aβ oligomerization and inhibit Aβ toxicity. Understanding the mechanism of these CTFs, especially Aβ(39-42), is of significance for future therapeutic development of AD and peptidomimetic-based drug development. Here we used ion mobility spectrometry-mass spectrometry to investigate the interactions between two modified Aβ(39-42) derivatives, VVIA-NH2 and Ac-VVIA, and full-length Aβ42. VVIA-NH2 was previously shown to inhibit Aβ toxicity, whereas Ac-VVIA did not. Our mass spectrometry analysis revealed that VVIA-NH2 binds directly to Aβ42 monomer and small oligomers while Ac-VVIA binds only to Aβ42 monomer. Ion mobility studies showed that VVIA-NH2 modulates Aβ42 oligomerization by not only inhibiting the dodecamer formation but also disaggregating preformed Aβ42 dodecamer. Ac-VVIA also inhibits and removes preformed Aβ42 dodecamer. However, the Aβ42 sample with the addition of Ac-VVIA clogged the nanospray tip easily, indicating that larger aggregates are formed in the solution in the presence of Ac-VVIA. Molecular dynamics simulations suggested that VVIA-NH2 binds specifically to the C-terminal region of Aβ42 while Ac-VVIA binds dispersedly to multiple regions of Aβ42. This work implies that C-terminal interactions and binding to Aβ oligomers are important for C-terminal fragment inhibitors.

Original languageEnglish (US)
Pages (from-to)1615-1623
Number of pages9
JournalJournal of Physical Chemistry B
Volume120
Issue number8
DOIs
StatePublished - Mar 3 2016

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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