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bioRxiv · 10.1101/2024.09.05.611426

Membrane-assisted Aβ40 aggregation pathways

Muhammedkutty, F. N. K.·Zhou, H.-X.
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Abstract

Alzheimers disease (AD) is caused by the assembly of amyloid-beta (A{beta}) peptides into oligomers and fibrils. Endogenous A{beta} aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here we used extensive MD simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of A{beta}40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded {beta}-sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight {beta}- sheet (residues Q15-D23) and a bent {beta}-sheet (residues A30-V36). This work presents the first comprehensive picture of membrane-assisted aggregation of A{beta}40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.

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Muhammedkutty, F. N. K., Zhou, H.-X.. 2024-09-08. Membrane-assisted Aβ40 aggregation pathways. https://doi.org/10.1101/2024.09.05.611426

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