Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains.
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-resolu...
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ftunivcam:oai:www.repository.cam.ac.uk:1810/346435 2023-07-30T04:00:20+02:00 Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. 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 2023-02-13T16:00:22Z text/xml application/pdf https://doi.org/10.17863/CAM.93856 https://www.repository.cam.ac.uk/handle/1810/346435 en eng Springer Science and Business Media LLC http://dx.doi.org/10.1007/s00401-022-02533-1 Acta Neuropathol doi:10.17863/CAM.93856 https://www.repository.cam.ac.uk/handle/1810/346435 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 Article 2023 ftunivcam https://doi.org/10.17863/CAM.93856 2023-07-10T21:14:37Z 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. Article in Journal/Newspaper Arctic Apollo - University of Cambridge Repository Arctic |
institution |
Open Polar |
collection |
Apollo - University of Cambridge Repository |
op_collection_id |
ftunivcam |
language |
English |
topic |
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 |
spellingShingle |
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 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 Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. |
topic_facet |
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 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
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 |
author_facet |
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 |
author_sort |
Yang, Yang |
title |
Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. |
title_short |
Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. |
title_full |
Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. |
title_fullStr |
Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. |
title_full_unstemmed |
Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. |
title_sort |
cryo-em structures of amyloid-β filaments with the arctic mutation (e22g) from human and mouse brains. |
publisher |
Springer Science and Business Media LLC |
publishDate |
2023 |
url |
https://doi.org/10.17863/CAM.93856 https://www.repository.cam.ac.uk/handle/1810/346435 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
doi:10.17863/CAM.93856 https://www.repository.cam.ac.uk/handle/1810/346435 |
op_doi |
https://doi.org/10.17863/CAM.93856 |
_version_ |
1772810842540081152 |