Structural basis for Aβ1–42 toxicity inhibition by Aβ C-terminal fragments: discrete molecular dynamics study.

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