The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide.
The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide.
复制标题
DOI：
10.1371/journal.pone.0035443
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Voss JC
中科院分区：
文献类型：
--
作者：
Petrlova J;Kálai T;Maezawa I;Altman R;Harishchandra G;Hong HS;Bricarello DA;Parikh AN;Lorigan GA;Jin LW;Hideg K;Voss JC
淀粉样蛋白β (a β)肽的沉积和寡聚化在阿尔茨海默病（AD）的发病机制中起关键作用。β肽是由β和γ分泌酶切割淀粉样前体蛋白（APP）的膜相关结构域产生的。一些证据表明，可溶性Aβ寡聚物（Aβ o）是AD病因学中主要的神经毒性物质。最近，我们已经证明了一类芴分子特异性地破坏了a β o物种。为了更好地了解这种破坏能力的作用机制，我们扩展了电子顺磁共振（EPR）光谱在a β肽中定位自旋标签的应用，以研究芴化合物对a β o结构和动力学的结合和影响。此外，我们还合成了一种含有硝基吡啶的自旋标记芴（SLF），它既能增强细胞对a β o毒性的保护作用，又能直接观察芴与a β o组装体的结合。我们还评估了芴靶向涉及神经退行性级联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物种形成的能力。用硝基吡啶修饰的芴在对抗Aβ肽毒性方面可能特别有用，因为它们具有抗氧化特性和破坏Aβ o的能力。
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 diminish the formation of intracellular AβO species. 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.
登录
查看更多内容
影响因子：
3.5
作者：
Liao, M. Q.;Tzeng, Y. J.;Chen, Y. C.
通讯作者：
Chen, Y. C.
影响因子：
4.2
作者：
Hong, Hyun-Seok;Maezawa, Izumi;Budamagunta, Madhu;Rana, Sandeep;Shi, Aibin;Vassar, Robert;Liu, Ruiwu;Lam, Kit S.;Cheng, R. Holland;Hua, Duy H.;Voss, John C.;Jin, Lee-Way
通讯作者：
Jin, Lee-Way
DOI：
10.1124/jpet.107.127167
发表时间：
2007-10-01
影响因子：
3.5
作者：
Mandal, Rajarsi;Kutala, Vijay Kumar;Kuppusamy, Periannan
通讯作者：
Kuppusamy, Periannan
影响因子：
4.7
作者：
Hong HS;Rana S;Barrigan L;Shi A;Zhang Y;Zhou F;Jin LW;Hua DH
通讯作者：
Hua DH
影响因子：
3.1
作者：
Lee, CW;Kung, MP;Kung, HF
通讯作者：
Kung, HF