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

• 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 HW
• Format: Article in Journal/Newspaper
• Language: English
• Published: Springer Science and Business Media LLC 2023
• Subjects: Alzheimer’s disease; Amyloid-beta; Arctic mutation; Electron cryo-microscopy; Mouse App NL−G−F knock-in line; Tau; Humans; Mice; Animals; Alzheimer Disease; Cryoelectron Microscopy; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Brain; Mutation; Transgenic; Arctic
• Online Access: https://doi.org/10.17863/CAM.93856; https://www.repository.cam.ac.uk/handle/1810/346435

Funder: Biotechnology and Biological Sciences Research Council; doi: http://dx.doi.org/10.13039/501100000268 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.