Published In
Acs Omega
Document Type
Article
Publication Date
2-7-2026
Subjects
Aggregation, Fluorescence, Magnetic properties -- Metals, Peptides and proteins
Abstract
Metal dyshomeostasis, particularly involving Cu2+, is increasingly recognized as a key contributor to amyloid-β (Aβ) aggregation and neurotoxicity in Alzheimer’s disease, motivating the development of chelators capable of selectively disrupting pathogenic metal-Aβ interactions without perturbing essential biological metals. Here, we employ steady-state fluorescence anisotropy as a real-time probe of TAMRA-Aβ1–42 rotational mobility to quantify metal-induced aggregation and its reversibility by two chelators with distinct selectivities: EDTA, a broad-spectrum benchmark, and Ni-bme-dach, a sulfur-rich metallodithiolate with high Cu affinity. Cu2+ induces the most significant increases in anisotropy, consistent with rapid formation of large nanoscale aggregates, while Fe3+ produces moderate aggregation and Zn2+ has minimal effect across pH 6.5 and 8.0. EDTA fully reverses Cu2+-induced aggregation but does so nonselectively, accompanied by pronounced fluorescence hyper-recovery indicative of broad metal stripping and fluorophore-environment perturbation. In contrast, Ni-bme-dach selectively extracts Cu2+, restoring monomer-like anisotropy at both pH values without hyper-recovery. UV–vis spectroscopy confirms formation of a discrete [Cu2-(Ni-bme-dach)3] complex, while TEM and AFM corroborate anisotropy trends and reveal a clear hierarchy of chelation responsiveness: Cu (fully reversible) > Fe (partially reversible) ≫ Zn (negligible). Together, these results establish fluorescence anisotropy as a sensitive kinetic platform for benchmarking chelator selectivity and demonstrate that Cu-driven Aβ aggregation is uniquely and selectively reversible. This work highlights metal-specific reversibility as a critical design principle for next-generation, Cu-targeted chelation strategies in Alzheimer’s disease.
Rights
Copyright (c) 2026 The Authors
This work is licensed under a Creative Commons Attribution 4.0 International License.
DOI
10.1021/acsomega.5c11345
Persistent Identifier
https://archives.pdx.edu/ds/psu/44484
Publisher
American Chemical Society (ACS)
Citation Details
Schroeder, A. N., Adams, E. K., Frost, D. C., Lopez, E., Giacomini, J. R., & Mackiewicz, M. R. (2026). Selective Reversal of Cu-Amyloid Aggregation Monitored in Real Time by Fluorescence Anisotropy: Ni-Bme-Dach vs EDTA Benchmarks. ACS Omega.