Abstract
BackgroundThe deposition and oligomerization of amyloid β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). Aβ peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by β and γ secretases. Several lines of evidence point to the soluble Aβ oligomer (AβO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the AβO species.Methodology/Principal FindingsTo 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 Aβ peptide to investigate the binding and influence of fluorene compounds on AβO 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 AβO toxicity and a route to directly observe the binding of the fluorene to the AβO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block AβO toxicity, scavenge free radicals and diminish the formation of intracellular AβO species.ConclusionsFluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they posses both antioxidant properties and the ability to disrupt AβO species.
Highlights
Alzheimer’s disease (AD) is characterized by the deposition of various amyloid b (Ab) aggregates forming amyloid in the brain
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 Ab oligomer (AbO) species
spin-labeled fluorene (SLF) protect against AbO toxicity in cultured neurons As demonstrated earlier [6,8] K01-162 attenuates intracellular
Summary
Alzheimer’s disease (AD) is characterized by the deposition of various amyloid b (Ab) aggregates forming amyloid in the brain. This spin-labeled fluorene (SLF) exerts similar potency in AbO disruption and protection against AbO-induced toxicity, while having superior free radical scavenging compared to the model fluorene compounds. To test the efficacy of SLFs to block Ab toxicity in cultured neurons, we examined the potential of a recently described class of SLF molecules to influence the survivability of MC65 neuroblastoma cells [16] containing conditional expression of the C-terminal region (C99) of the amyloid precursor protein (APP).
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