Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses.
Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses.
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DOI：
10.1021/cb900112v
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发表时间：
2009-08-21
影响因子：
4
通讯作者：
Nilsson, K. Peter R.
中科院分区：
文献类型：
--
作者：
Aslund, Andreas;Sigurdson, Christina J.;Klingstedt, Therese;Grathwohl, Stefan;Bolmont, Tristan;Dickstein, Dara L.;Glimsdal, Eirik;Prokop, Stefan;Lindgren, Mikael;Konradsson, Peter;Holtzman, David M.;Hof, Patrick R.;Heppner, Frank L.;Gandy, Samuel;Jucker, Mathias;Aguzzi, Adriano;Hammarstrom, Per;Nilsson, K. Peter R.
选择性鉴定蛋白质聚集体的分子探针对于促进我们对脑淀粉样变性的分子发病机制的理解具有重要意义。在这里，我们报道了五聚硫吩衍生物的化学设计，称为发光共轭低聚硫吩衍生物(LCoS)，可用于通过多光子显微镜实时显示转基因小鼠神经退行性疾病模型中的脑蛋白质聚集体。其中一种LCoS，p-FTAA，表现出构象相关的光学性质，并可用于两个小鼠适应的Pron菌株的不同Pron沉积的体外光谱指认。P-FTAA还显示在Aβ多肽的体外纤颤过程中，瞬时可溶的纤维前非亲硫黄素Aβ-集合体被染色。在脑组织样本中，p-β的强荧光可以很容易地识别出A-FTs沉积和神经原纤维缠结(NFT)，并且Lco染色显示与常规抗体(6E10和AT8)完全共存，表明p-FTAA可以检测到阿尔茨海默病中所有免疫阳性的聚集蛋白物种，但成像时间明显比免疫荧光短(100倍)。此外，抗寡聚体A11抗体在与p-β共染色时发现单个A-β斑块呈斑块状的胰岛状染色，提示前纤维样物可能是人脑A-FPA斑块的固有成分。阿尔茨海默病的主要特征，即Aβ聚集体和NFT也可以区分开来，因为p-FTAA的发射光谱不同。总之，我们证明LCoS可以作为研究蛋白质聚集性疾病的强大实用研究工具，并有助于研究淀粉样蛋白的起源、进化和成熟、Aβ−tau相互作用以及体内和体外的发病机制。
Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying cerebral amyloidoses. Here we report the chemical design of pentameric thiophene derivatives, denoted luminescent conjugated oligothiophenes (LCOs), which could be used for real-time visualization of cerebral protein aggregates in transgenic mouse models of neurodegenerative diseases by multiphoton microscopy. One of the LCOs, p-FTAA, showed conformation-dependent optical properties and could be utilized for ex vivo spectral assignment of distinct prion deposits from two mouse-adapted prion strains. p-FTAA also revealed staining of transient soluble pre-fibrillar non-thioflavinophilic Aβ- assemblies during in vitro fibrillation of Aβ peptides. In brain tissue samples, Aβ deposits and neurofibrillary tangles (NFTs) were readily identified by a strong fluorescence from p-FTAA and the LCO staining showed complete co-localization with conventional antibodies (6E10 and AT8), indicating that p-FTAA detects all the immuno-positive aggregated proteinaceous species in Alzheimer disease, but with significantly shorter imaging time (100 fold) compared to immunofluorescence. In addition, a patchy islet-like staining of individual Aβ plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA, suggesting that pre-fibrillar species are likely an intrinsic component of Aβ plaques in human brain. The major hallmarks of Alzheimer’s disease, namely Aβ aggregates versus NFTs could also be distinguished due to distinct emission spectra from p-FTAA. Overall, we demonstrate that LCOs can be utilized as powerful practical research tools for studying protein aggregation diseases and facilitate the study of amyloid origin, evolution and maturation, Aβ−tau interactions and pathogenesis both ex vivo and in vivo.
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影响因子：
3.2
作者：
Nilsson, K. Peter R.;Hammarstrom, Per;Inganas, Olle
通讯作者：
Inganas, Olle
影响因子：
2.9
作者：
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影响因子：
16.6
作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
3
作者：
Groenning, Minna;Norrman, Mathias;Frokjaer, Sven
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Frokjaer, Sven