Structural Basis for Aβ1-42 Toxicity Inhibition by Aβ C-Terminal Fragments: Discrete Molecular Dynamics Study

Amyloid beta-protein (A beta) is central to the pathology of Alzheimer's disease. Of the two predominant A beta alloforms, A beta(1-40) and A beta(1-42), the latter forms more toxic oligomers. C-terminal fragments (CTFs) of A beta were recently shown to inhibit A beta(1-42) toxicity in vitro. Here, we studied A beta(1-42) assembly in the presence of three effective CTF inhibitors and an ineffective fragment, A beta(21-30). Using a discrete molecular dynamics approach that recently was shown to capture key differences between A beta(1-40) and A beta(1-42) oligomerization, we compared A beta(1-42) oligomer formation in the absence and presence of CTFs or A beta(21-30) and identified structural elements of A beta(1-42) that correlated with A beta(1-42) toxicity. CTFs co-assembled with A beta(1-42) into large heterooligomers containing multiple A beta(1-42) and inhibitor fragments. In contrast, A beta(21-30) co-assembled with A beta(1-42) into heterooligomers containing mostly a single A beta(1-42) and multiple A beta(21-30) fragments. The CITs, but not A beta(21-30), decreased the beta-strand propensity of A beta(1-42) in a concentration-dependent manner. CTFs and A beta(21-30) had a high binding propensity to the hydrophobic regions of A beta(1-42), but only CTFs were found to bind the A beta(1-42) region A2-F4.Consequently, only CTFs but not A beta(21-30) reduced the solvent accessibility of A beta(1-42) in region D1-R5. The reduced solvent accessibility of A beta(1-42) in the presence of CTFs was comparable to the solvent accessibility of A beta(1-40) oligomers formed in the absence of A beta fragments. These findings suggest that region D1-R5, which was more exposed to the solvent in A beta(1-42) than in A beta(1-40) oligomers, is involved in mediating A beta(1-42) oligomer neurotcodcity. (C) 2011 Elsevier Ltd. All rights reserved.