Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains

Yang, Y.; Zhang, W.; Murzin, A. G.; Schweighauser, M.; Huang, M.; Lovestam, S.; Peak-Chew, S. Y.; Saito, T.; Saido, T. C.; McDonald, J.; Lavenir, I.; Ghetti, B.; Graff, C.; Kumar, A.; Nordberg, A.; Goedert, M.; Scheres, S. H.

doi:10.1101/2022.11.07.515410

bioRxiv · 10.1101/2022.11.07.515410

Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains

Yang, Y.·Zhang, W.·Murzin, A. G.·Schweighauser, M.·Huang, M.·Lovestam, S.·Peak-Chew, S. Y.·Saito, T.·Saido, T. C.·McDonald, J.·Lavenir, I.·Ghetti, B.·Graff, C.·Kumar, A.·Nordberg, A.·Goedert, M.·Scheres, S. H.

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Abstract

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-{beta} (A{beta})], causes dominantly inherited Alzheimers disease. Here we report the high-resolution cryo-EM structures of A{beta} filaments from the frontal cortex of a previously described case (A{beta}PParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II A{beta}42. When compared to the structures of wild-type A{beta}42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant A{beta} molecules and promote filament formation. A minority of A{beta}42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of A{beta} filaments with the Arctic mutation from mouse knock-in line AppNL-G-F. Most filaments are made of two identical mutant protofilaments that extend from D1-G37 (murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The murine Arctic fold differs from the human Arctic folds, but shares some substructure.

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Yang, Y., Zhang, W., Murzin, A. G., Schweighauser, M., Huang, M., Lovestam, S., Peak-Chew, S. Y., Saito, T., Saido, T. C., McDonald, J., Lavenir, I., Ghetti, B., Graff, C., Kumar, A., Nordberg, A., Goedert, M., Scheres, S. H.. 2022-11-07. Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains. https://doi.org/10.1101/2022.11.07.515410

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