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.
|
Authors | Michael R Jones, Changhua Mu, Michael C P Wang, Michael I Webb, Charles J Walsby, Tim Storr |
Journal | Metallomics : integrated biometal science
(Metallomics)
Vol. 7
Issue 1
Pg. 129-35
(Jan 2015)
ISSN: 1756-591X [Electronic] England |
PMID | 25387614
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Amyloid
- Amyloid beta-Peptides
- Indazoles
- Organometallic Compounds
- Ruthenium Compounds
- indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III))
|
Topics |
- Alzheimer Disease
- Amyloid
(drug effects, metabolism)
- Amyloid beta-Peptides
(metabolism)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Humans
- Indazoles
(pharmacology)
- Organometallic Compounds
(pharmacology)
- Ruthenium Compounds
|