Issue 6, 2024

Rigidifying of the internal dynamics of amyloid-beta fibrils generated in the presence of synaptic plasma vesicles

Abstract

We investigated the changes in internal flexibility of amyloid-β1–40 (Aβ) fibrils grown in the presence of rat synaptic plasma vesicles. The fibrils are produced using a modified seeded growth protocol, in which the Aβ concentration is progressively increased at the expense of the decreased lipid to protein ratio. The morphologies of each generation are carefully assessed at several fibrils’ growth time points using transmission electron microscopy. The side-chain dynamics in the fibrils is investigated using deuterium solid-state NMR measurements, with techniques spanning line shapes analysis and several NMR relaxation rates measurements. The dynamics is probed in the site-specific fashion in the hydrophobic C-terminal domain and the disordered N-terminal domain. An overall strong rigidifying effect is observed in comparison with the wild-type fibrils generated in the absence of the membranes. In particular, the overall large-scale fluctuations of the N-terminal domain are significantly reduced, and the activation energies of rotameric inter-conversion in methyl-bearing side-chains of the core (L17, L34, M35, V36), as well as the ring-flipping motions of F19 are increased, indicating a restricted core environment. Membrane-induced flexibility changes in Aβ aggregates can be important for the re-alignment of protein aggregates within the membrane, which in turn would act as a disruption pathway of the bilayers’ integrity.

Graphical abstract: Rigidifying of the internal dynamics of amyloid-beta fibrils generated in the presence of synaptic plasma vesicles

Supplementary files

Article information

Article type
Paper
Submitted
05 okt 2023
Accepted
22 jan 2024
First published
22 jan 2024

Phys. Chem. Chem. Phys., 2024,26, 5466-5478

Rigidifying of the internal dynamics of amyloid-beta fibrils generated in the presence of synaptic plasma vesicles

L. Vugmeyster, D. F. Au, B. Frazier, W. Qiang and D. Ostrovsky, Phys. Chem. Chem. Phys., 2024, 26, 5466 DOI: 10.1039/D3CP04824A

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