A new water-soluble Cu(II) chelator that retrieves Cu from Cu(amyloid-β) species, stops associated ROS production and prevents Cu(II)‐induced Aβ aggregation

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

“…As a prototypical ligand with an appropriate Cu( ii ) over Zn( ii ) selectivity (log( S L 2 ) = 7.7, i.e. S L 2 > S Aβ ) 44,46 we have used a water-soluble Schiff base derivative noted as L 2 (in green in Scheme 1) and compare its properties to those of a control ligand noted as Lc (in red in Scheme 1) having an appropriate Cu( ii ) affinity (log( K Cu ) = 2.4) but an inappropriate selectivity (log( S Lc ) = 2.0, i.e. S Lc < S Aβ ).…”

“…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.…”

“…However, in the presence of Zn( ii ), most of them mainly extract Zn( ii ) but not Cu( ii ) from the peptide; in other words, despite having a stronger affinity for Cu( ii ), they are rather selective for Zn( ii ). Only Schiff base derivatives 39 such as the L 2 ligand described here 44 have the ability to remove Cu( ii ) despite the presence of Zn( ii ). Indeed, to remove Cu( ii ) from Aβ in the presence of Zn( ii ), it is not enough that the chelator has a higher Cu( ii ) affinity than the Aβ.…”

pH-dependent kinetics of copper ions binding to amyloid-β peptide

“…Cu 2+ is generally believed to exert oxidative disturbances by generating reactive oxygen species (ROS) via the Haber-Weiss and Fenton-like reactions [4], whereas the contribution of the Aβ−Cu 2+ complex to AD pathogenesis remains debatable. Some studies support the idea that Cu 2+ binding to Aβ results in the reduction of free Cu 2+ , and its ability to engage in ROS-generating chemistry [5,6]. Other studies show that Cu 2+ bound to Aβ is more neurotoxic than unbound Cu 2+ [7][8][9], as the former induces fibrous and amorphous aggregates of Aβ, which leads to the generation of ROS, and increases neurotoxicity to neurons [10,11].…”