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

The mechanism of A beta aggregation in the absence of metal ions is well established, yet the role that Zn2+ and Cu2+, the two most studied metal ions, released during neurotransmission, paly in promoting A beta aggregation in the vicinity of neuronal synapses remains elusive. Here we report the kinetics of Zn2+ binding to A beta and Zn"/Cu" binding to A beta -Cu to form ternary complexes under near physiological conditions (nM AA /./M metal ions). We find that these reactions are several orders of magnitude slower than Cu2+ binding to Afl. Coupled reaction-diffusion simulations of the interactions of synaptically released metal ions with Afi show that up to a third of Afi is Cu21.-bound under repetitive metal ion release, while any other A beta -metal complexes (including A beta-Zn) are insignificant. We therefore conclude that Zn' is unlikely to play an important role in the very early stages (i.e., dimer formation) of Afi aggregation, contrary to a widely held view in the subject. We propose that targeting the specific interactions between Cu' and A beta may be a viable option in drug development efforts for early stages of AD.