Mapping ApoE/Aβ binding regions to guide inhibitor discovery.

Blocking the interaction between the E4 isoform of apolipoprotein E (ApoE) and amyloid beta-peptide (A beta) may be an avenue for pharmacological intervention in Alzheimer's disease (AD). The main regions of interaction of the two proteins are, respectively, ApoE244-272 and A beta 12-28. These protein segments are too large to facilitate the design of small molecule inhibitors. We mapped the primary components of ApoE/A beta interaction to smaller peptide segments. Within the three motifs that are primarily responsible for ApoE/A beta interaction, we identified four peptides that substantially block ApoE/A beta interaction and further improved their inhibitory activity by rational hydrophobic amino acid substitution. Moreover, the mapping results provide the clue that the A beta residues which interact with ApoE appear to be in the same region where A beta self-interacts. According to this information, we found that Congo Red and X-34 could strongly inhibit ApoE/A beta interaction. Our findings extend our understanding of ApoE/A beta interaction and may guide the discovery of inhibitors that treat AD by antagonizing ApoE/A beta interaction.