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

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

SUBMITTER: Zheng X 

PROVIDER: S-EPMC4777659 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature