Selective Reversal of Cu-Amyloid Aggregation Monitored in Real Time by Fluorescence Anisotropy: Ni-Bme-Dach vs EDTA Benchmarks.

Authors

Alyssa N Schroeder, Eleanor K Adams, Dane C Frost, Erica Lopez, Jennie R Giacomini, Marilyn R Mackiewicz

Published in

ACS omega. Volume 11. Issue 7. Pages 12810-12823. Feb 24, 2026. Epub Feb 07, 2026.

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-Aβ_1-42 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.

PMID:
41768703
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.

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