%0 Journal Article
%T The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the A¦Â Peptide
%A Jitka Petrlova
%A Tam¨¢s K¨¢lai
%A Izumi Maezawa
%A Robin Altman
%A Ghimire Harishchandra
%A Hyun-Seok Hong
%A Daniel A. Bricarello
%A Atul N. Parikh
%A Gary A. Lorigan
%A Lee-Way Jin
%A K¨¢lm¨¢n Hideg
%A John C. Voss
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0035443
%X Background The deposition and oligomerization of amyloid ¦Â (A¦Â) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). A¦Â peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by ¦Â and ¦Ã secretases. Several lines of evidence point to the soluble A¦Â oligomer (A¦ÂO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the A¦ÂO species. Methodology/Principal Findings To achieve a better understanding of the mechanism of action of this disruptive ability, we extend the application of electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels in the A¦Â peptide to investigate the binding and influence of fluorene compounds on A¦ÂO structure and dynamics. In addition, we have synthesized a spin-labeled fluorene (SLF) containing a pyrroline nitroxide group that provides both increased cell protection against A¦ÂO toxicity and a route to directly observe the binding of the fluorene to the A¦ÂO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block A¦ÂO toxicity, scavenge free radicals and diminish the formation of intracellular A¦ÂO species. Conclusions Fluorene modified with pyrroline nitroxide may be especially useful in counteracting A¦Â peptide toxicity, because they posses both antioxidant properties and the ability to disrupt A¦ÂO species.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035443