Kinetic Analysis Reveals the Identity of Aβ-Metal Complex Responsible for the Initial Aggregation of Aβ in the Synapse

[Image: see text] The mechanism of Aβ aggregation in the absence of metal ions is well established, yet the role that Zn(2+) and Cu(2+), the two most studied metal ions, released during neurotransmission, paly in promoting Aβ aggregation in the vicinity of neuronal synapses remains elusive. Here we report the kinetics of Zn(2+) binding to Aβ and Zn(2+)/Cu(2+) binding to Aβ-Cu to form ternary complexes under near physiological conditions (nM Aβ, μM metal ions). We find that these reactions are several orders of magnitude slower than Cu(2+) binding to Aβ. Coupled reaction-diffusion simulations of the interactions of synaptically released metal ions with Aβ show that up to a third of Aβ is Cu(2+)-bound under repetitive metal ion release, while any other Aβ-metal complexes (including Aβ-Zn) are insignificant. We therefore conclude that Zn(2+) is unlikely to play an important role in the very early stages (i.e., dimer formation) of Aβ aggregation, contrary to a widely held view in the subject. We propose that targeting the specific interactions between Cu(2+) and Aβ may be a viable option in drug development efforts for early stages of AD.