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Early Divergence in Misfolding Pathways of Amyloid-Beta Peptides.


ABSTRACT: The amyloid cascade hypothesis proposes that amyloid-beta (Aβ) aggregation is the initial triggering event in Alzheimer's disease. Here, we utilize NMR spectroscopy and monitor the structural dynamics of two variants of Aβ, Aβ40 and Aβ42, as a function of temperature. Despite having identical amino acid sequence except for the two additional C-terminal residues, Aβ42 has higher aggregation propensity than Aβ40. As revealed by the NMR data on dynamics, including backbone chemical shifts, intra-methyl cross-correlated relaxation rates and glycine-based singlet-states, the C-terminal region of Aβ, especially the G33-L34-M35 segment, plays a particular role in the early steps of temperature-induced Aβ aggregation. In Aβ42, the distinct dynamical behaviour of C-terminal residues at higher temperatures is accompanied with marked changes in the backbone dynamics of residues V24-K28. The distinctive role of the C-terminal region of Aβ42 in the initiation of aggregation defines a target for the rational design of Aβ42 aggregation inhibitors.

SUBMITTER: Mamone S 

PROVIDER: S-EPMC8596873 | biostudies-literature |

REPOSITORIES: biostudies-literature

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