Zn impacts Cu coordination to amyloid-β, the Alzheimer's peptide, but not the ROS production and the associated cell toxicity

Abstract

Combined coordination of Zn(II) and Cu(I) or Cu(II) to the amyloid-β peptide has been investigated using XANES, EPR and NMR spectroscopies. While Zn(II) does alter Cu(II) binding to Aβ, this has no effect on (Aβ)Cu induced ROS production and associated cell toxicity.

How Zn can impede Cu detoxification by chelating agents in Alzheimer's disease: a proof-of-concept study

“…Such ROS production can be studied by proven methods (Scheme S3†) 35,44,52 that rely either on the UV monitoring of consumption of ascorbate (Asc) (Fig. 3) or on the detection of the fluorescent 7-OH-CCA formed by a reaction between the HO˙ produced and the 3-CCA (Fig.…”

“…In the presence of Aβ, regardless the co-presence of Zn( ii ), Asc consumption is decreased compared to free Cu( i / ii ), as previously observed and discussed. 35,44 Curves (c) in panels A and B recorded in the absence of Zn( ii ) show that L 2 (panel A) is able to stop Asc consumption by Cu(Aβ) while Lc (panel B) can slow it down. Note that just after the addition of the L 2 (curve (c), panel A), there is an increase in the absorbance due to the formation of the Cu(L 2 ) complex that absorbs at 265 nm, the wavelength where the Asc consumption is monitored.…”

“…23. This issue has also been discussed concerning the chelation of metal ions bound to Aβ in a 3-partner system (Aβ and the two metal ions) 22,34,35 and sometimes inferred for the 4-partner system (see e.g. ref.…”

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

“…Interestingly, although the two divalent metal ions share a number of the same coordination ligands [17,18,30,47,50,51,69], there are marked differences in the influence of Zn 2+ and Cu 2+ on Aβ misfolding, as outlined in Table 1. In particular, substoichiometric Cu 2+ accelerates Aβ fibre growth [48,49], while substoichiometric Zn 2+ shows a reduced total fibre growth for both alloforms.…”

“…We have investigated the effect of a range of Cu 2+ and Zn 2+ mixtures on Aβ assemblies, as both are present extracellularly at the synapse, and share histidine coordinating ligands. Cu 2+ is not displaced by the presence of Zn 2+ but the coordination geometry is influenced by the presence of Zn 2+ [50,51].…”