title: Mechanistic investigation of the inhibition of Abeta42 assembly and neurotoxicity by Abeta42 C-terminal fragments.
abstract: Oligomeric forms of amyloid beta-protein (Abeta) are key neurotoxins in Alzheimer's disease (AD). Previously, we found that C-terminal fragments (CTFs) of Abeta42 interfered with assembly of full-length Abeta42 and inhibited Abeta42-induced toxicity. To decipher the mechanism(s) by which CTFs affect Abeta42 assembly and neurotoxicity, here, we investigated the interaction between Abeta42 and CTFs using photoinduced cross-linking and dynamic light scattering. The results demonstrate that distinct parameters control CTF inhibition of Abeta42 assembly and Abeta42-induced toxicity. Inhibition of Abeta42-induced toxicity was found to correlate with stabilization of oligomers with a hydrodynamic radius (R(H)) of 8-12 nm and attenuation of formation of oligomers with an R(H) of 20-60 nm. In contrast, inhibition of Abeta42 paranucleus formation correlated with CTF solubility and the degree to which CTFs formed amyloid fibrils themselves but did not correlate with inhibition of Abeta42-induced toxicity. Our findings provide important insight into the mechanisms by which different CTFs inhibit the toxic effect of Abeta42 and suggest that stabilization of nontoxic Abeta42 oligomers is a promising strategy for designing inhibitors of Abeta42 neurotoxicity.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, 635 Charles E.Young Drive S., Los Angeles, CA 90095, USA.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Li
authors.forename: Bernhard H
authors.initials: BH
authors.lastname: Monien
authors.forename: Aleksey
authors.initials: A
authors.lastname: Lomakin
authors.forename: Reeve
authors.initials: R
authors.lastname: Zemel
authors.forename: Erica A
authors.initials: EA
authors.lastname: Fradinger
authors.forename: Miao
authors.initials: M
authors.lastname: Tan
authors.forename: Sean M
authors.initials: SM
authors.lastname: Spring
authors.forename: Brigita
authors.initials: B
authors.lastname: Urbanc
authors.forename: Cui-Wei
authors.initials: CW
authors.lastname: Xie
authors.forename: George B
authors.initials: GB
authors.lastname: Benedek
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D010446:Peptide Fragments / Q000494:pharmacology*; D055503:Protein Multimerization; D055550:Protein Stability; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments