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

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

SUBMITTER: Branch T 

PROVIDER: S-EPMC5609119 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature