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

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...

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Bibliographic Details
Published in:Acta Neuropathologica
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: Text
Language:English
Published: Springer Berlin Heidelberg 2023
Subjects:
Original Paper
Arctic
Online Access:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925504/
http://www.ncbi.nlm.nih.gov/pubmed/36611124
https://doi.org/10.1007/s00401-022-02533-1
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Summary: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 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02533-1.

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