Oligomeric Protein Complexes Formed by Beta Amyloid Peptides and Their Molecular Associates

The aggregation and dysregulation of beta-amyloid (A beta) peptides are critical factors in the pathogenesis of Alzheimer's disease (AD). This study investigates the use of reverse micelles (RMs) as a nanoscale environment to encapsulate A beta peptides and explore their interactions with zinc ions (Zn2(+)) and a TDP-43 variant, both of which are important binding partners of A beta peptides closely associated with neurodegenerative diseases. We demonstrate that RMs stabilize A beta peptides in their oligomeric form, promoting beta-sheet formation and enabling detailed structural studies using solid-state NMR. Our findings reveal that Zn2(+) induces specific conformational changes in residues E11 and E22 of A beta oligomers but not E3, and that the TDP-43 variant can form stable protein complex with A beta 40, that persists even after extended incubation and sonication. A systematic comparison of the site-specific 13C chemical shifts of the A beta 40 oligomers modulated by the interactions with Zn2(+), A beta 42, and a TDP-43 variant, revealed that A beta 40 predominantly adopts a beta 1-loop-beta 2 motif. Notably, chemical state changes were mainly observed in the residues within the loop region and the charged residues of the beta 1 region. In contrast, the hydrophobic residues of the beta-sheet regions were structurally unaltered upon protein complex formation.