加州大學(xué)戴維斯分校生物化學(xué)與分子生物學(xué)系的John C. Voss等人近日在《公共科學(xué)圖書館·綜合》（PLoS ONE）雜志發(fā)表論文稱，已研制出可阻斷阿爾茨海默病發(fā)生通路的小分子物質(zhì),。
淀粉樣蛋白β（Aβ）的沉積和寡聚化在阿爾茨海默?。ˋD）的發(fā)生中起重要作用。淀粉樣前體蛋白的膜相關(guān)性結(jié)構(gòu)域被β和γ分泌酶分解時即可產(chǎn)生Aβ肽段。有多種證據(jù)表明，可溶性Aβ寡聚物（AβO）是AD病因?qū)W的首要神經(jīng)毒性物質(zhì)。芴化合物是一種3環(huán)小分子,，最初被作為造影劑用于在PET中檢測淀粉樣蛋白。之前有研究稱,，除檢測淀粉樣蛋白外,，芴化合物還可結(jié)合于Aβ，引起Aβ結(jié)構(gòu)不穩(wěn)定,，從而進(jìn)一步減少淀粉樣蛋白的形成,。最近，John C. Voss等人稱,，他們已證實一種芴化合物可特異性地破壞AβO,，從而阻斷阿爾茨海默病的發(fā)生。
由于生物分子并不能發(fā)出可供電子順磁共振（EPR）檢測的信號,，研究者對芴化合物附加了一種特殊的分子--硝基氧自旋標(biāo)記物（可發(fā)出被EPR檢測的特殊信號）,，從而使其活性在EPR光譜中更加顯著。
研究者發(fā)現(xiàn),，自旋標(biāo)記的芴化合物對Aβ的阻斷比未標(biāo)記的芴化合物更加有效,。此外，硝基氧具有抗氧化能力,，可清除造成神經(jīng)細(xì)胞損傷并引起炎癥的氧自由基,，從而更好地保護(hù)神經(jīng)細(xì)胞,。
Voss說，現(xiàn)已證實自旋標(biāo)記的芴化合物具有以下重要屬性：在影像學(xué)研究中用于檢測淀粉樣蛋白,，抑制Aβ的形成,，減少炎癥反應(yīng)。因此,，該物質(zhì)在阿爾茨海默病的研究,、診斷和治療中具有重大潛能。（生物谷bioon.com）
doi:10.1371/journal.pone.0035443
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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.
