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

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 ( A β PPar...

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Príomhchruthaitheoirí: Yang Yang, Wenjuan Zhang, Alexey G. Murzin, Manuel Schweighauser, Melissa Huang, Sofia Lövestam, Sew‐Yeu Peak‐Chew, Takashi Saito, Takaomi C. Saido, Jennifer A. Macdonald, Isabelle Lavenir, Bernardino Ghetti, Caroline Graff, Amit Kumar, Agneta Nordberg, Michel Goedert, Sjors H. W. Scheres
Formáid: Artigo
Teanga:Béarla
Foilsithe / Cruthaithe: 2023
Rochtain ar líne:https://doi.org/10.1007/s00401-022-02533-1
https://link.springer.com/content/pdf/10.1007/s00401-022-02533-1.pdf
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Achoimre: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 ( 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.

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