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

Abstract

The aggregation and dysregulation of β-amyloid (Aβ) 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 Aβ peptides and explore their interactions with zinc ions (Zn²⁺) and a TDP-43 variant, both of which are important binding partners of Aβ peptides closely associated with neurodegenerative diseases. We demonstrate that RMs stabilize Aβ peptides in their oligomeric form, promoting β-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 Aβ oligomers but not E3, and that the TDP-43 variant can form stable protein complex with Aβ₄₀, that persists even after extended incubation and sonication. A systematic comparison of the site-specific ¹³C chemical shifts of the Aβ₄₀ oligomers modulated by the interactions with Zn²⁺, Aβ₄₂, and a TDP-43 variant, revealed that Aβ₄₀ predominantly adopts a β₁-loop-β₂ motif. Notably, chemical state changes were mainly observed in the residues within the loop region and the charged residues of the β₁ region. In contrast, the hydrophobic residues of the β-sheet regions were structurally unaltered upon protein complex formation.

Keywords: beta‐amyloid; protein‐protein interaction; reverse micelle; solid‐state NMR.