Mechanistic Investigation of the Inhibition of Aβ42 Assembly and Neurotoxicity by Aβ42 C-terminal Fragments
Author(s)Li, Huiyuan; Monien, Bernhard H.; Lomakin, Aleksey; Zemel, Reeve; Fradinger, Erica A.; Tan, Miao; Spring, Sean M.; Urbanc, Brigita; Xie, Cui-Wei; Benedek, George B.; Bitan, Gal; ... Show more Show less
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Oligomeric forms of amyloid β-protein (Aβ) are key neurotoxins in Alzheimer’s disease (AD). Previously, we found that C-terminal fragments (CTFs) of Aβ42 interfered with assembly of full-length Aβ42 and inhibited Aβ42-induced toxicity. To decipher the mechanism(s) by which CTFs affect Aβ42 assembly and neurotoxicity, here, we investigated the interaction between Aβ42 and CTFs using photoinduced cross-linking and dynamic light scattering. The results demonstrate that distinct parameters control CTF inhibition of Aβ42 assembly and Aβ42-induced toxicity. Inhibition of Aβ42-induced toxicity was found to correlate with stabilization of oligomers with a hydrodynamic radius (R[subscript H]) of 8−12 nm and attenuation of formation of oligomers with an R[subscript H] of 20−60 nm. In contrast, inhibition of Aβ42 paranucleus formation correlated with CTF solubility and the degree to which CTFs formed amyloid fibrils themselves but did not correlate with inhibition of Aβ42-induced toxicity. Our findings provide important insight into the mechanisms by which different CTFs inhibit the toxic effect of Aβ42 and suggest that stabilization of nontoxic Aβ42 oligomers is a promising strategy for designing inhibitors of Aβ42 neurotoxicity.
DepartmentMassachusetts Institute of Technology. Department of Physics
American Chemical Society (ACS)
Li, Huiyuan et al. “Mechanistic Investigation of the Inhibition of Aβ42 Assembly and Neurotoxicity by Aβ42 C-Terminal Fragments.” Biochemistry 49.30 (2010): 6358–6364. © 2010 American Chemical Society
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