title: Mechanism of C-Terminal Fragments of Amyloid β-Protein as Aβ Inhibitors: Do C-Terminal Interactions Play a Key Role in Their Inhibitory Activity?
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.
authors.affiliation: Department of Chemistry and Biochemistry and ∥Department of Physics, University of California , Santa Barbara, California 93106, United States.|Department of Neurology, David Geffen School of Medicine, §Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and Biochemistry and ∥Department of Physics, University of California , Santa Barbara, California 93106, United States.|Department of Neurology, David Geffen School of Medicine, §Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Chemistry and Biochemistry and ∥Department of Physics, University of California , Santa Barbara, California 93106, United States.|Department of Neurology, David Geffen School of Medicine, §Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Deyu
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry and ∥Department of Physics, University of California , Santa Barbara, California 93106, United States.|Department of Neurology, David Geffen School of Medicine, §Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry and ∥Department of Physics, University of California , Santa Barbara, California 93106, United States.|Department of Neurology, David Geffen School of Medicine, §Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.affiliation: Department of Chemistry and Biochemistry and ∥Department of Physics, University of California , Santa Barbara, California 93106, United States.|Department of Neurology, David Geffen School of Medicine, §Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.affiliation: Department of Chemistry and Biochemistry and ∥Department of Physics, University of California , Santa Barbara, California 93106, United States.|Department of Neurology, David Geffen School of Medicine, §Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D057786:Peptidomimetics; D066329:Protein Aggregates; C570535:amyloid beta-peptide (39-42); C075222:amyloid beta-protein (1-42)