Jump to main content
Jump to site search

Issue 1, 2015
Previous Article Next Article

Modulation of the Aβ peptide aggregation pathway by KP1019 limits Aβ-associated neurotoxicity

Author affiliations

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that is increasing worldwide due to increased life expectancy. AD is characterized by two pathological hallmarks in the brain: amyloid-β (Aβ) plaque deposits and neurofibrillary tangles. A focus of AD research has concentrated on either inhibiting Aβ peptide aggregation that leads to plaque formation or breaking down pre-formed Aβ peptide aggregates. An alternative approach is to modulate the Aβ aggregation profile by facilitating the formation of Aβ species that are off-pathway and non-toxic. Herein, we report the re-purposing of the widely studied Ru(III) anti-cancer complex KP1019, towards regulating the aggregation profile of the Aβ peptide. Using electron paramagnetic resonance (EPR) spectroscopy, we conclude that KP1019 binds to histidine residues, located at the N-terminus of the peptide, in a rapid and robust fashion. Native gels and transmission electron microscopy (TEM) analyses have provided insight into the species and structures that are generated by KP1019-Aβ interactions. Finally, incubation in an in vitro human neuronal cell model has demonstrated that the formation of KP1019-Aβ species rescues cell viability from Aβ-associated neurotoxicity. Modulation of the Aβ aggregation pathway via covalent interactions with small molecules is thus a promising AD therapeutic strategy.

Graphical abstract: Modulation of the Aβ peptide aggregation pathway by KP1019 limits Aβ-associated neurotoxicity

Back to tab navigation

Supplementary files

Publication details

The article was received on 24 Sep 2014, accepted on 31 Oct 2014 and first published on 03 Nov 2014


Article type: Paper
DOI: 10.1039/C4MT00252K
Citation: Metallomics, 2015,7, 129-135
  •   Request permissions

    Modulation of the Aβ peptide aggregation pathway by KP1019 limits Aβ-associated neurotoxicity

    M. R. Jones, C. Mu, M. C. P. Wang, M. I. Webb, C. J. Walsby and T. Storr, Metallomics, 2015, 7, 129
    DOI: 10.1039/C4MT00252K

Search articles by author

Spotlight

Advertisements