Journal
ACTA NEUROPATHOLOGICA
Volume 145, Issue 3, Pages 325-333Publisher
SPRINGER
DOI: 10.1007/s00401-022-02533-1
Keywords
Alzheimer's disease; Amyloid-beta; Arctic mutation; Electron cryo-microscopy; Mouse App(NL-G-F) knock-in line; Tau
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The high-resolution cryo-EM structures of A beta filaments with the Arctic mutation were reported in this study. Most of the filaments consist of two pairs of non-identical protofilaments, sharing a common substructure with the folds of type I and type II A beta 42. There are subtle conformational changes in the human Arctic folds, which may be due to the lack of a side chain at G22.
The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-beta (A beta)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of A beta filaments from the frontal cortex of a previously described case (A beta 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 beta 42. When compared to the structures of wild-type A beta 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 beta molecules and promote filament formation. A minority of A beta 42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of A beta 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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