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Kinetic analysis reveals the identity of Aβ-metal complex responsible for the initial aggregation of Aβ in the synapse

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Title: Kinetic analysis reveals the identity of Aβ-metal complex responsible for the initial aggregation of Aβ in the synapse
Authors: Branch, T
Barahona, M
Dodson, C
Ying, L
Item Type: Journal Article
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.
Issue Date: 16-Jun-2017
Date of Acceptance: 16-Jun-2017
URI: http://hdl.handle.net/10044/1/49341
DOI: https://dx.doi.org/10.1021/acschemneuro.7b00121
ISSN: 1948-7193
Publisher: American Chemical Society
Start Page: 1970
End Page: 1979
Journal / Book Title: ACS Chemical Neuroscience
Volume: 8
Issue: 9
Copyright Statement: © 2017 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html)
Sponsor/Funder: The Leverhulme Trust
Funder's Grant Number: RPG-2015-345
Keywords: Kinetics
amyloid-β-metal ion complex
fluorescence
neuronal synapse
reaction-diffusion simulation
stopped-flow
Publication Status: Published
Appears in Collections:Mathematics
National Heart and Lung Institute
Applied Mathematics and Mathematical Physics
Faculty of Medicine
Faculty of Natural Sciences



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