Mechanism of C-Terminal Fragments of Amyloid $\beta$-Protein as A$\beta$ Inhibitors: Do C-Terminal Interactions Play a Key Role in Their Inhibitory Activity?

TitleMechanism of C-Terminal Fragments of Amyloid $\beta$-Protein as A$\beta$ Inhibitors: Do C-Terminal Interactions Play a Key Role in Their Inhibitory Activity?
Publication TypeJournal Article
Year of Publication2016
AuthorsZheng X, Wu C, Liu D, Li H, Bitan G, Shea J-E, Bowers MThomas
JournalJournal of Physical Chemistry B
Volume120
Issue8
Start Page1615
Pagination1615-1623
Date Published03/2016
ISSN1520-5207
Keywords21975, CNSI/MRL, CSC, FBNS02, MRL, NIH, NSF, Shea, TACC, UCLA, XSEDE
Abstract

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

URLhttp://dx.doi.org/10.1021/acs.jpcb.5b08177
DOI10.1021/acs.jpcb.5b08177
Grant: 
MRI R2 (CNS-0960316), CSC, MRL (DMR-1121053)