Background: The b-amyloid peptide (Ab) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that hasbeen proposed to form a “glycine zipper” that drives the formation of toxic Ab oligomers. We have tested thishypothesis by examining the toxicity of Ab 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 Ab toxicity in all models tested, as measuredby cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiplemodels that Ab Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycinezipper formation blocks assembly of toxic Ab oligomers. To test this model rigorously, we engineered second sitesubstitutions in Ab predicted by the glycine zipper model to compensate for the Gly37Leu substitution andexpressed these in C. elegans. We show that these second site substitutions restore in vivo Abtoxicity, furthersupporting the glycine zipper model.Conclusions: Our structure/function studies support the view that the glycine zipper motif present in the Cterminalportion of Ab plays an important role in the formation of toxic Ab oligomers. Compounds designed tointerfere specifically with formation of the glycine zipper could have therapeutic potential