A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo

Background: The beta-amyloid peptide (A beta) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that has been proposed to form a glycine zipper that drives the formation of toxic A beta oligomers. We have tested this hypothesis by examining the toxicity of A beta variants containing substitutions in this motif using a neuronal cell line, primary neurons, and a transgenic C. elegans model. Results: We found that a Gly37Leu substitution dramatically reduced A beta toxicity in all models tested, as measured by cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiple models that A beta Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycine zipper formation blocks assembly of toxic A beta oligomers. To test this model rigorously, we engineered second site substitutions in A beta predicted by the glycine zipper model to compensate for the Gly37Leu substitution and expressed these in C. elegans. We show that these second site substitutions restore in vivo A beta toxicity, further supporting the glycine zipper model. Conclusions: Our structure/function studies support the view that the glycine zipper motif present in the C-terminal portion of A beta plays an important role in the formation of toxic A beta oligomers. Compounds designed to interfere specifically with formation of the glycine zipper could have therapeutic potential.