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 (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.

Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer’s Disease Mouse Models

“…Interestingly, similarities can be observed between murine type III fibrils and human Arctic (E693G, E22G in Aβ) Aβ filaments [21] (Fig. 3A).…”

“…Commonly used animal models are transgenic mice that mimic different clinical characteristics of the disease [20]. The structures of Aβ fibrils extracted from two different mouse models, the knock-in APP NL-G-F and the knock-in APP NL-F , were recently determined by cryo-EM [18], [21], [22]. While the APP NL-F Aβ42 fibril resembles the human type II Aβ42 fold, the fold of the APP NL-G-F Aβ42(E22G) fibrils differs from fibrils extracted from human brain.…”

Disease-relevant β2-microglobulin variants share a common amyloid fold

“…The β 2 m variants studied here in vitro have different effects in vivo, with distinct human pathology associated with each: an iatrogenic joint arthropathy for β 2 m-ΔN6; a familial, systemic amyloidosis for β 2 m-D76N; and an iatrogenic deposition in the tongue and salivary glands for β 2 m-V27M. It is tempting, therefore, to hypothesise that the self-assembly of these different variants would result in different amyloid folds, especially given recent data showing that the 'arctic' sequence variant of Aβ (E22G) forms a different fibril structure ex vivo 57,58 than that observed for the WT-Aβ sequence 16 . The data presented here suggests this may not necessarily be the case for β 2 m and its variants.…”

RNA as a component of fibrils from Alzheimer’s disease and other neurodegenerations

“…Data for this study were sourced from public repositories, the EMDB 19 and the PDB 20 . Cryo-EM maps and protein models of fibrils from autopsy brains of patients with the following neurodegenerative diseases were examined: AD 1–5,15,37,46 , AGD 13 , ALS-FTLD 7 , CTE 9 , CBD 3,10 , DLB 6 , FTLD-TDP 14,16 , GSS 12,18 , GGT 13 , MSA 11,15 , PD 6,17 , PiD 8 , PART 4 , PSP 13,16 and PrP-CAA 12 . The proteins involved were Abeta 37,46 , alpha-synuclein 6,11 , PrP 18 , tau 1–5,8–10,12,13,16 , TDP-43 7 and TMEM106B 14–17 .…”

“…Cryo-EM maps and protein models of fibrils from autopsy brains of patients with the following neurodegenerative diseases were examined: AD 1–5,15,37,46 , AGD 13 , ALS-FTLD 7 , CTE 9 , CBD 3,10 , DLB 6 , FTLD-TDP 14,16 , GSS 12,18 , GGT 13 , MSA 11,15 , PD 6,17 , PiD 8 , PART 4 , PSP 13,16 and PrP-CAA 12 . The proteins involved were Abeta 37,46 , alpha-synuclein 6,11 , PrP 18 , tau 1–5,8–10,12,13,16 , TDP-43 7 and TMEM106B 14–17 . A majority of fibrils had EDs, as determined by inspection and reference to the published papers.…”