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

• Published in: Acta neuropathologica Vol. 145; no. 3; pp. 325 - 333
• Main Authors: Yang, Yang, Zhang, Wenjuan, Murzin, Alexey G., Schweighauser, Manuel, Huang, Melissa, Lövestam, Sofia, Peak-Chew, Sew Y., Saito, Takashi, Saido, Takaomi C., Macdonald, Jennifer, Lavenir, Isabelle, Ghetti, Bernardino, Graff, Caroline, Kumar, Amit, Nordberg, Agneta, Goedert, Michel, Scheres, Sjors H. W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2023; Springer Nature B.V
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Brain - metabolism; Cortex (frontal); Cryoelectron Microscopy; Filaments; Humans; Hydrogen bonding; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Mutants; Mutation; Mutation - genetics; Neurodegenerative diseases; Neurosciences; Original Paper; Pathology; Tau protein; β-Amyloid; Arctic region; Arctic mutation; Alzheimer’s disease; Mouse; knock-in line; Tau; Electron cryo-microscopy; Amyloid-beta; Mouse App NL−G−F knock-in line
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-022-02533-1

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 ( A β 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 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 App NL−G−F . Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 ( App NL−G−F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The App NL−G−F murine Arctic fold differs from the human Arctic folds, but shares some substructure.