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, Aβ1–40 and Aβ1–42, the latter forms more toxic oligomers. C-terminal fragments (CTFs) of Aβ were recently shown to inhibit Aβ1–42 toxicity in vitro. Here, we studied Aβ1–42 assembly in the presence of three effective CTF inhibitors and an ineffective fragment, Aβ21–30. Using a discrete molecular dynamics approach that recently was shown to capture key differences between Aβ1–40 and Aβ1–42 oligomerization, we compared Aβ1–42 oligomer formation in the absence and presence of CTFs or Aβ21–30 and identified structural elements of Aβ1–42 that correlated with Aβ1–42 toxicity. CTFs co-assembled with Aβ1–42 into large heterooligomers containing multiple Aβ1–42 and inhibitor fragments. In contrast, Aβ21–30 co-assembled with Aβ1–42 into heterooligomers containing mostly a single Aβ1–42 and multiple Aβ21–30 fragments. The CTFs, but not Aβ21–30, decreased the β-strand propensity of Aβ1–42 in a concentration-dependent manner. CTFs and Aβ21–30 had a high binding propensity to the hydrophobic regions of Aβ1–42, but only CTFs were found to bind the Aβ1–42 region A2–F4. Consequently, only CTFs but not Aβ21–30 reduced the solvent accessibility of Aβ1–42 in region D1–R5. The reduced solvent accessibility of Aβ1–42 in the presence of CTFs was comparable to the solvent accessibility of Aβ1–40 oligomers formed in the absence of Aβ fragments. These findings suggest that region D1–R5, which was more exposed to the solvent in Aβ1–42 than in Aβ1–40 oligomers, is involved in mediating Aβ1–42 oligomer neurotoxicity.

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