TY  - JOUR
TI  - Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains
EP  - 333
SP  - 325
AV  - public
KW  - Science & Technology
KW  -  Life Sciences & Biomedicine
KW  -  Clinical Neurology
KW  -  Neurosciences
KW  -  Pathology
KW  -  Neurosciences & Neurology
KW  -  Alzheimer's disease
KW  -  Amyloid-beta
KW  -  Arctic mutation
KW  -  Electron cryo-microscopy
KW  -  Mouse App(NL-G-F) knock-in line
KW  -  Tau
KW  -  HEREDITARY CEREBRAL-HEMORRHAGE
KW  -  BEAM-INDUCED MOTION
KW  -  ALZHEIMERS-DISEASE
KW  -  GENE
KW  -  PEPTIDES
VL  - 145
N2  - The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-? (A?)], causes dominantly inherited Alzheimer?s disease. Here, we report the high-resolution cryo-EM structures of A? filaments from the frontal cortex of a previously described case (A?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 A?42. When compared to the structures of wild-type A?42 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 A? molecules and promote filament formation. A minority of A?42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of A? 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.
JF  - Acta Neuropathologica
UR  - https://doi.org/10.1007/s00401-022-02533-1
PB  - SPRINGER
N1  - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
IS  - 3
Y1  - 2023/01/07/
ID  - discovery10168368
SN  - 0001-6322
A1  - Yang, Yang
A1  - Zhang, Wenjuan
A1  - Murzin, Alexey G
A1  - Schweighauser, Manuel
A1  - Huang, Melissa
A1  - Lovestam, Sofia
A1  - Peak-Chew, Sew Y
A1  - Saito, Takashi
A1  - Saido, Takaomi C
A1  - Macdonald, Jennifer
A1  - Lavenir, Isabelle
A1  - Ghetti, Bernardino
A1  - Graff, Caroline
A1  - Kumar, Amit
A1  - Nordberg, Agneta
A1  - Goedert, Michel
A1  - Scheres, Sjors HW
ER  -