Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates

Authors

Tom Scheidt, University of Cambridge
Urszula Lapinska, University of Cambridge
Janet R. Kumita, University of CambridgeFollow
Daniel Whiten, University of Wollongong, University of CambridgeFollow
David Klenerman, University of Cambridge
Mark R. Wilson, University of WollongongFollow
Samuel Cohen, University of Cambridge
Sara Linse, Lund University
Michele Vendruscolo, University of Cambridge
Christopher M. Dobson, University of CambridgeFollow
Tuomas P. J Knowles, University of Cambridge
Paolo Arosio, University of Cambridge, ETH Zurich

RIS ID

135293

Publication Details

Scheidt, T., Lapinska, U., Kumita, J. R., Whiten, D. R., Klenerman, D., Wilson, M. R., Cohen, S. I. A., Linse, S., Vendruscolo, M., Dobson, C. M., Knowles, T. P. J. & Arosio, P. (2019). Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates. Science Advances, 5 (4), eaau3112-1-eaau3112-9.

Abstract

The aggregates of the Ab peptide associated with Alzheimer's disease are able to both grow in size aswell as generate, through secondary nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: The Brichos domain, which suppresses specifically secondary nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Ab fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.