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

• Main Authors: Yang, Yang, Zhang, Wenjuan, Murzin, Alexey G, Schweighauser, Manuel, Huang, Melissa, Lovestam, 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 2023
• Subjects: Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; Neurosciences; Pathology; Neurosciences & Neurology; Alzheimer's disease; Amyloid-beta; Arctic mutation; Electron cryo-microscopy; Mouse App(NL-G-F) knock-in line; Tau; HEREDITARY CEREBRAL-HEMORRHAGE; BEAM-INDUCED MOTION; ALZHEIMERS-DISEASE; GENE; PEPTIDES; Arctic
• Online Access: https://discovery.ucl.ac.uk/id/eprint/10168368/1/s00401-022-02533-1.pdf; https://discovery.ucl.ac.uk/id/eprint/10168368/

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.