On the ability of CuAβ1-x peptides to form ternary complexes: Neurotransmitter glutamate is a competitor while not a ternary partner

• The ternary complex formation by amyloid beta (Aβ) peptides is an important issue.
• We studied interactions of Cu(II) complex of Aβ1–16 with Glu by several techniques.
• The absence of ternary Aβ1–16Glu complexes was demonstrated.
• Glu is able to compete for Cu(II) with Aβ1–16 under biologically relevant conditions.
• We discuss general rules for formation of ternary complexes of Aβ1–16 and Cu(II)

In the light of conflicting reports on the ability of copper(II) complexes of amyloid beta (Aβ) peptides to form ternary complexes with small molecules co-present in the biological milieu, we performed a study of coordination equilibria in the system containing Cu(II) ions, the Aβ1–16 peptide, glutamic acid and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid, HEPES) buffer. Using potentiometry, isothermal titration calorimetry (ITC), UV–visible spectroscopy and EPR, we concluded that glutamic acid was not able to form such a ternary complex, but can efficiently compete for the Cu(II) ion with the Aβ peptide at Glu concentrations relevant for the synaptic cleft. We also found that the literature constants for Cu(II) complexes with Glu were overestimated, but this effect was partially compensated by the formation of a ternary Cu(Glu)(HEPES) complex. Our results indicate that small molecules co-present with Cu(II) ions and Aβ peptides in the synaptic cleft are not very likely to enhance Cu(II)/Aβ interactions, but instead should be considered as a Cu(II) buffering system that may help prevent these interactions and participate in Cu(II) clearance from the synaptic cleft.

Graphical AbstractInteractions of amyloid beta (Aβ1–16), Cu(II) and glutamate were studied by potentiometry, ITC, UV–vis and EPR, demonstrating the absence of ternary Aβ1–16Glu complexes. Instead, Glu was found to compete for Cu(II) with Aβ1–16 under biologically relevant conditions. These results suggest a general rule for formation of ternary of Aβ1–16/Cu(II) complexesFigure optionsDownload as PowerPoint slide