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

Abstract

The mechanism of Aβ 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 Aβ aggregation in the vicinity of neuronal synapses remains elusive. Here we report the kinetics of Zn²⁺ binding to Aβ and Zn²⁺/Cu²⁺ 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 Cu²⁺ 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 Cu²⁺-bound under repetitive metal ion release, while any other Aβ-metal complexes (including Aβ-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 Aβ aggregation, contrary to a widely held view in the subject. We propose that targeting the specific interactions between Cu²⁺ and Aβ may be a viable option in drug development efforts for early stages of AD.

Keywords: Kinetics; amyloid-β-metal ion complex; fluorescence; neuronal synapse; reaction-diffusion simulation; stopped-flow.