The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide

Background: The deposition and oligomerization of amyloid beta (A beta) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). A beta peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by beta and gamma secretases. Several lines of evidence point to the soluble A beta oligomer (A beta O) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the A beta O 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 beta peptide to investigate the binding and influence of fluorene compounds on A beta O 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 beta O toxicity and a route to directly observe the binding of the fluorene to the A beta O 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 beta O toxicity, scavenge free radicals and diminish the formation of intracellular A beta O species. Conclusions: Fluorene modified with pyrroline nitroxide may be especially useful in counteracting A beta peptide toxicity, because they posses both antioxidant properties and the ability to disrupt A beta O species.