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

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Author(s): Fonte Virginia | Dostal Vishantie | Roberts Christine | Gonzales Patrick | Lacor Pascale | Magrane Jordi | Dingwell Natalie | Fan Emily | Silverman Michael | Stein Gretchen | Link Christopher

Journal: Molecular Neurodegeneration
ISSN 1750-1326

Volume: 6;
Issue: 1;
Start page: 61;
Date: 2011;
Original page

Keywords: Alzheimer's disease | C. elegans | pore-forming toxin | glycine motif

ABSTRACT
Abstract Background The β-amyloid peptide (Aβ) 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 Aβ oligomers. We have tested this hypothesis by examining the toxicity of Aβ 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 Aβ toxicity in all models tested, as measured by cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiple models that Aβ Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycine zipper formation blocks assembly of toxic Aβ oligomers. To test this model rigorously, we engineered second site substitutions in Aβ 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 Aβtoxicity, 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 Aβ plays an important role in the formation of toxic Aβ oligomers. Compounds designed to interfere specifically with formation of the glycine zipper could have therapeutic potential.
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