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

Background: The deposition and oligomerization of amyloid b (Ab) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). Ab peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by b and c secretases. Several lines of evidence point to the soluble Ab oligomer (AbO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the AbO 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 Ab peptide to investigate the binding and influence of fluorene compounds on AbO 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 AbO toxicity and a route to directly observe the binding of the fluorene to the AbO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block AbO toxicity, scavenge free radicals and diminish the formation of intracellular AbO species. Conclusions: Fluorene modified with pyrroline nitroxide may be especially useful in counteracting Ab peptide toxicity, because they posses both antioxidant properties and the ability to disrupt AbO species. [ABSTRACT FROM AUTHOR]