A new structural model of Alzheimer’s Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling

Abstract

Brain deposition of Aβ in the form of amyloid plaques is a pathological hallmark of Alzheimer's disease. There are two major species of Aβ in the brain: Aβ42 and Aβ40. Although Aβ40 is several-fold more abundant than Aβ42 in soluble form, Aβ42 is the major component of amyloid plaques. Structural knowledge of Aβ42 fibrils is important both for understanding the process of Aβ aggregation and for designing fibril-targeting drugs. Here we report site-specific structural information of Aβ42 fibrils at 22 residue positions based on electron paramagnetic resonance data. In combination with structure prediction program Rosetta, we modeled Aβ42 fibril structure at atomic resolution. Our Aβ42 fibril model consists of four parallel in-register β-sheets: βN (residues ~7-13), β1 (residues ~17-20), β2 (residues ~32-36), and βC (residues 39-41). The region of β1-loop-β2 in Aβ42 fibrils adopts similar structure as that in Aβ40 fibrils. This is consistent with our cross seeding data that Aβ42 fibril seeds shortened the lag phase of Aβ40 fibrillization. On the other hand, Aβ42 fibrils contain a C-terminal β-arc-β motif with a special turn, termed “arc”, at residues 37-38, which is absent in Aβ40 fibrils. Our results can explain both the higher aggregation propensity of Aβ42 and the importance of Aβ42 to Aβ40 ratio in the pathogenesis of Alzheimer's disease.

Cross‐seeding between Aβ40 and Aβ42 in Alzheimer's disease

“…This b1-turn-b2 motif is the core structure of Ab40 fibrils. For the structure of Ab42 fibrils, our own studies using electron paramagnetic resonance suggest that the same b1-turn-b2 motif also exists in Ab42 fibrils [17]. We also found that Ab42 fibrils contain a turn at residues 37-38 and a C-terminal b-sheet at residues 39-41, which constitute the major difference between Ab40 and Ab42 fibrils.…”

“… mentioned that ‘polymorphic Aβ42 fibrils prepared in vitro do not seed the growth of Aβ40 fibrils’, but no data were shown. On the other hand, seven other reports concluded that Aβ42 fibrils can seed the aggregation of Aβ40, but these reports did not meet all four technical points (Table ). In terms of Aβ42 cross‐seeding, Cukalevski et al .…”

“…Lu et al [26] mentioned that 'polymorphic Ab42 fibrils prepared in vitro do not seed the growth of Ab40 fibrils', but no data were shown. On the other hand, seven other reports concluded that Ab42 fibrils can seed the aggregation of Ab40, but these reports [12][13][14][15][16][17][18] did not meet all four technical points ( Table 1). In terms of Ab42 cross-seeding, Cukalevski et al [24] showed that the half time of Ab42 aggregation was not affected by Ab40 seeds, while four other studies [12][13][14]19] support an opposite view (Table 1).…”

“…Therefore, it is important to resolve the conflicting observations on this subject so that proper conclusions can be made. Our literature search showed that there are 11 previous reports [12][13][14][15][16][17][18][19][24][25][26]] that investigated the cross-seeding between Ab40 and Ab42, with conflicting conclusions. We believe that four technical points are critical for a rigorous investigation on this topic: (a) Source of Ab should be recombinant expression, instead of chemical synthesis.…”

“…Indeed, Ab40 inhibits amyloid deposition of Ab42 in vivo [10] and slows down the aggregation of Ab42 in vitro [11,12]. Preformed fibrils of Ab40 and Ab42 can promote each other's aggregation [12][13][14][15][16][17][18][19]. Furthermore, Gu and Guo [20] show that Ab40 and Ab42, when mixed together, form interlaced fibrils, supporting that Ab40 and Ab42 interact at molecular level.…”