Modified EDTA selectively recognized Cu2+ and its application in the disaggregation of β-amyloid-Cu (II)/Zn (II) aggregates

Abstract

The accumulation of the β-amyloid (Aβ) aggregates induced by Cu2+/Zn2+ in conjunction with toxicity is closely related to Alzheimer's disease (AD). Herein, we intended to improve the efficiency and selectivity of traditional chelator ethylenediaminetetraacetic acid (EDTA) combined with a fluorescent group 4-aminosalicylic acid (4-ASA)to acquire a novel potential chelator 4,4′-((2,2′-(ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(acetyl))bis(azanediyl))bis(2-hydroxybenzoic acid) (EDTA-ASA) capable of disaggregating Aβ-Cu(II)/ Zn(II) aggregates. EDTA-ASA combines 4-ASA as fluorophore and multidentate amino nitrogen, hydroxyl and carboxyl groups to chelate Cu2+ from Aβ-Cu (II) aggregates. The specific selectivity of EDTA-ASA towards Cu2+ in Tris-HCl buffer solution was investigated by fluorescence measurements. It exhibits high recognition towards Cu2+ with no significant interference of other competitive metal ions, which overcomes the deficiencies of EDTA. Importantly, the binding sites and binding mode for Cu2+ were clarified through DFT calculations. The thioflavin-T (ThT) fluorescence analyses and transmission electron microscopy (TEM) results have revealed EDTA-ASA exhibited an enhanced disaggregation capability on Aβ-Cu (II)/Zn (II) aggregates in comparison to EDTA. The Cu2+ chelating affinity was sufficient for EDTA-ASA to sequester Cu2+ from Aβ-Cu (II) aggregates.