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.

Multiple intermediates were found in Cu(ii) binding to Aβ4–16 before the formation of a tight complex.

Gravity-sensitive cellular responses are regularly observed in both specialized and nonspecialized cells. One potential mechanism for this sensitivity is a changing viscosity of the intracellular organelles. Here, we report a novel, to our knowledge, viscosity-sensitive molecular rotor based on mesosubstituted boron-dipyrrin used to investigate the response of viscosity of cellular membranes to hypergravity conditions created at the large diameter centrifuge at the European Space Agency Technology Centre. Mouse osteoblastic (MC3T3-E1) and endothelial (human umbilical vein endothelial cell) cell lines were tested, and an increase in viscosity was found with increasing hypergravity loading. This response is thought to be primarily biologically driven, with the potential for a small, instantaneous physical mechanism also contributing to the observed effect. This work provides the first, to our knowledge, quantitative data for cellular viscosity changes under hypergravity, up to 15 Â g.

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.