Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America.
PLoS One. 2012;7(4):e35443. doi: 10.1371/journal.pone.0035443. Epub 2012 Apr 30.
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.
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 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.
Fluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they possess both antioxidant properties and the ability to disrupt AβO species.
淀粉样 β 肽（Aβ）的沉积和寡聚化在阿尔茨海默病（AD）的发病机制中起着关键作用。Aβ肽来源于淀粉样前体蛋白（APP）的膜相关结构域被β和γ分泌酶切割。有几条证据表明可溶性 Aβ寡聚体（AβO）是 AD 发病机制中主要的神经毒性物质。最近，我们已经证明了一类芴类分子可以特异性地破坏 AβO 物质。
方法/主要发现：为了更好地了解这种破坏能力的作用机制，我们将靶向自旋标记的电子顺磁共振（EPR）光谱法在 Aβ肽中的应用扩展到研究芴类化合物对 AβO 结构和动力学的结合和影响。此外，我们合成了一种含有吡咯啉氮氧自由基的自旋标记芴（SLF），它既能增加细胞对 AβO 毒性的保护，又能直接观察芴与 AβO 组装的结合。我们还评估了芴类化合物靶向神经退行性级联反应中涉及的多种病理过程的能力，例如它们阻断 AβO 毒性、清除自由基和减少细胞内 AβO 物质形成的能力。
用吡咯啉氮氧自由基修饰的芴类化合物可能特别有助于对抗 Aβ肽毒性，因为它们具有抗氧化特性和破坏 AβO 物质的能力。
