导读：芴化合物是一种3环小分子，最初被作为造影剂用于在PET中检测淀粉样蛋白。之前有研究称除检测淀粉样蛋白外，芴化合物还可结合于Aβ，引起Aβ结构不稳定，从而进一步减少淀粉样蛋白的形成。最近，John C. Voss等人称，他们已证实一种芴化合物可特异性地破坏AβO，从而阻断阿尔茨海默病的发生。
加州大学戴维斯分校生物化学与分子生物学系的John C. Voss等人近日在《公共科学图书馆•综合》（PLoS ONE）杂志发表论文称，已研制出可阻断阿尔茨海默病发生通路的小分子物质。
淀粉样蛋白β（Aβ）的沉积和寡聚化在阿尔茨海默病（AD）的发生中起重要作用。淀粉样前体蛋白的膜相关性结构域被β和γ分泌酶分解时即可产生Aβ肽段。有多种证据表明，可溶性Aβ寡聚物（AβO）是AD病因学的首要神经毒性物质。芴化合物是一种3环小分子，最初被作为造影剂用于在PET中检测淀粉样蛋白。之前有研究称，除检测淀粉样蛋白外，芴化合物还可结合于Aβ，引起Aβ结构不稳定，从而进一步减少淀粉样蛋白的形成。最近，John C. Voss等人称，他们已证实一种芴化合物可特异性地破坏AβO，从而阻断阿尔茨海默病的发生。
由于生物分子并不能发出可供电子顺磁共振（EPR）检测的信号，研究者对芴化合物附加了一种特殊的分子--硝基氧自旋标记物（可发出被EPR检测的特殊信号），从而使其活性在EPR光谱中更加显着。
研究者发现，自旋标记的芴化合物对Aβ的阻断比未标记的芴化合物更加有效。此外，硝基氧具有抗氧化能力，可清除造成神经细胞损伤并引起炎症的氧自由基，从而更好地保护神经细胞。
Voss说，现已证实自旋标记的芴化合物具有以下重要属性：在影像学研究中用于检测淀粉样蛋白，抑制Aβ的形成，减少炎症反应。因此，该物质在阿尔茨海默病的研究、诊断和治疗中具有重大潜能。
The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide
Jitka Petrlova, Tamás Kálai, Izumi Maezawa, Robin Altman, Ghimire Harishchandra, Hyun-Seok Hong, Daniel A. Bricarello, Atul N. Parikh, Gary A. Lorigan, Lee-Way Jin, Kálmán Hideg, John C. Voss.
Background 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. Conclusions Fluorene 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.
文献链接：https://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035443
