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

Abstract

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) 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 Aβ42. When compared to the structures of wild-type Aβ42 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 Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ 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 to G37 (AppNL-G-F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The AppNL-G-F murine Arctic fold differs from the human Arctic folds, but shares some substructure.

• Authors: Yang Yang, Wenjuan Zhang, Alexey G Murzin, Manuel Schweighauser, Melissa Huang, Sofia Lövestam, Sew Y Peak-Chew, Takashi Saito, Takaomi C Saido, Jennifer Macdonald, Isabelle Lavenir, Bernardino Ghetti, Caroline Graff, Amit Kumar, Agneta Nordberg, Michel Goedert, Sjors H W Scheres
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 145 Issue 3 Pg. 325-333 (03 2023) ISSN: 1432-0533 [Electronic] Germany
• PMID: 36611124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2023. The Author(s).

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor

Topics

• Humans
• Mice
• Animals
• Alzheimer Disease (metabolism)
• Cryoelectron Microscopy
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Brain (metabolism)
• Mutation (genetics)
• Mice, Transgenic