Mechanistic investigation of the inhibition of Abeta42 assembly and neurotoxicity by Abeta42 C-terminal fragments.
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.
Li
Huiyuan
H
Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, 635 Charles E.Young Drive S., Los Angeles, CA 90095, USA.
Monien
Bernhard H
BH
Lomakin
Aleksey
A
Zemel
Reeve
R
Fradinger
Erica A
EA
Tan
Miao
M
Spring
Sean M
SM
Urbanc
Brigita
B
Xie
Cui-Wei
CW
Benedek
George B
GB
Bitan
Gal
G
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
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments