The kinetics of the interactions between amyloid‐β (Aβ) and metal ions are crucial to understanding the physiological and pathological roles of Aβ in the normal brain and in Alzheimer’s disease. Using the quenching of a fluorescent probe by Cu2+, the mechanism of Aβ/Cu2+ interactions in physiologically relevant conditions has been elucidated. Cu2+ binds to Aβ at a near diffusion‐limited rate, initially forming component I. The switching between component I and II occurs on the second timescale, with a significant energy barrier. Component I is much more reactive towards Cu2+ ligands and likely responsible for initial Aβ dimer formation. Clioquinol (CQ) is shown to sequester Cu2+ more effectively than other tested ligands. These findings have implications for the potential roles of Aβ in regulating neurotransmission, and for the screening of small molecules targeting Aβ–metal interactions.
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.
Mutations and post‐translational modifications of amyloid‐β (Aβ) peptide in its N terminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two Aβ peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with Aβ peptide phosphorylated at serine 8 (pS8). All three peptides bind to copper with a similar rate as the wild‐type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50 % faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper‐bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of Aβ.
The kinetics of the interactions between amyloid‐β (Aβ) and metal ions are crucial to understanding the physiological and pathological roles of Aβ in the normal brain and in Alzheimer’s disease. Using the quenching of a fluorescent probe by Cu2+, the mechanism of Aβ/Cu2+ interactions in physiologically relevant conditions has been elucidated. Cu2+ binds to Aβ at a near diffusion‐limited rate, initially forming component I. The switching between component I and II occurs on the second timescale, with a significant energy barrier. Component I is much more reactive towards Cu2+ ligands and likely responsible for initial Aβ dimer formation. Clioquinol (CQ) is shown to sequester Cu2+ more effectively than other tested ligands. These findings have implications for the potential roles of Aβ in regulating neurotransmission, and for the screening of small molecules targeting Aβ–metal interactions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.