Modulation of the Aβ peptide aggregation pathway by KP1019 limits Aβ-associated neurotoxicity.
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.
Department of Chemistry, Simon Fraser University, Burnaby, BC V5A1S6, Canada. cwalsby@sfu.ca tim_storr@sfu.ca.
Michael R
MR
Jones
Changhua
C
Mu
Michael C P
MC
Wang
Michael I
MI
Webb
Charles J
CJ
Walsby
Tim
T
Storr
D000544:Alzheimer Disease; D000682:Amyloid / Q000187:drug effects* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D017975:Ruthenium Compounds
D000682:Amyloid; D016229:Amyloid beta-Peptides; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III))