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@article{Branch:2017:10.1021/acschemneuro.7b00121,
author = {Branch, T and Barahona, M and Dodson, C and Ying, L},
doi = {10.1021/acschemneuro.7b00121},
journal = {ACS Chemical Neuroscience},
pages = {1970--1979},
title = {Kinetic analysis reveals the identity of Aβ-metal complex responsible for the initial aggregation of Aβ in the synapse},
url = {http://dx.doi.org/10.1021/acschemneuro.7b00121},
volume = {8},
year = {2017}
}

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TY  - JOUR
AB  - 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.
AU  - Branch,T
AU  - Barahona,M
AU  - Dodson,C
AU  - Ying,L
DO  - 10.1021/acschemneuro.7b00121
EP  - 1979
PY  - 2017///
SN  - 1948-7193
SP  - 1970
TI  - Kinetic analysis reveals the identity of Aβ-metal complex responsible for the initial aggregation of Aβ in the synapse
T2  - ACS Chemical Neuroscience
UR  - http://dx.doi.org/10.1021/acschemneuro.7b00121
UR  - http://hdl.handle.net/10044/1/49341
VL  - 8
ER  -

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