Lee, Hsiang‐TingHsiang‐TingLeeChang, Han‐WenHan‐WenChangLin, Yeh‐TungYeh‐TungLinHuang, Shing‐JongShing‐JongHuangWu, Meng‐HsinMeng‐HsinWuTsai, Chang‐ShunChang‐ShunTsaiTu, Ling‐HsienLing‐HsienTuLee, Ming‐CheMing‐CheLeeChen, Yun‐RuYun‐RuChenCHUN-CHUNG CHAN2025-07-182025-07-182025-06-06https://scholars.lib.ntu.edu.tw/handle/123456789/730740The 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.enbeta-amyloidprotein-protein interactionreverse micellesolid-state NMR[SDGs]SDG3journal article10.1002/chem.202501099