NGUYEN, Phuong H.; CAMPANERA, Josep M.; NGO, Son Tung; LOQUET, Antoine; DERREUMAUX, Philippe

doi:10.1021/acs.jpcb.9b01206

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The journal of physical chemistry. B. 2019, vol. 123, n° 17, p. 3643-3648

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The amyloid-beta (Abeta) 42 oligomers are much more toxic than Abeta40 oligomers in Alzheimer's disease. Numerous experiments indicate that toxicity could involve the formation of pores in membranes, but experimental high-resolution structure determination of these pore-forming Abeta oligomers has been impeded by aggregate heterogeneity. Using extensive atomistic simulations, low-resolution data obtained in lipid bilayers, and other theoretical factors, we proposed atomic structures of Abeta40 and Abeta42 beta-barrels in a bilayer mimicking a neuronal membrane. The 3D model, which consists of tetramer subunits, two distinct beta-hairpin motifs and an asymmetric arrangement of eight antiparallel beta-strands, is drastically destabilized for Abeta40 compared to its Abeta42 counterpart. Our computational modeling has several implications in Alzheimer's disease, sheds light on the amyloid pore hypothesis, and explains the higher deleterious property of Abeta42.< Réduire

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Vesicles

Peptides and proteins

Oligomers

Membranes

Chemical structure

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Tetrameric Abeta40 and Abeta42 beta-Barrel Structures by Extensive Atomistic Simulations. I. In a Bilayer Mimicking a Neuronal Membrane

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