The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide.

PloS One
Jitka PetrlovaJohn C Voss

Abstract

The 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. 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 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 diminis...Continue Reading

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Citations

Mar 25, 2014·European Journal of Medicinal Chemistry·Tamás KálaiKálmán Hideg
May 27, 2015·International Journal of Molecular Sciences·Xueling DaiZhaofeng Jiang
Dec 3, 2016·Journal of Alzheimer's Disease : JAD·Silvia HiltJohn C Voss
Aug 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Silvia HiltJohn C Voss
Sep 15, 2018·The Journal of Physical Chemistry. C, Nanomaterials and Interfaces·Silvia HiltJohn C Voss

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Methods Mentioned

BETA
electron paramagnetic resonance
AFM
Circular dichroism
Fluorescence
Assay

Software Mentioned

Nanoscope
Veeco

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