Mechanistic Investigation of the Inhibition of Aβ42 Assembly and Neurotoxicity by Aβ42 C-terminal Fragments

Abstract

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.