Intermediate antiparallel beta structure in amyloid plaques revealed by infrared spectroscopic imaging.
Intermediate antiparallel beta structure in amyloid plaques revealed by infrared spectroscopic imaging.
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红外光谱成像揭示淀粉样斑块中的中间反平行β结构。
DOI：
10.1101/2023.04.18.537414
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ghosh,Ayanjeet
中科院分区：
文献类型：
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作者：
Holcombe,Brooke;Foes,Abigail;Banerjee,Siddhartha;Yeh,Kevin;Wang,Shih-HsiuJ;Bhargava,Rohit;Ghosh,Ayanjeet
淀粉样β（Aβ）肽聚集到细胞外斑块中是阿尔茨海默病（AD）的分子病理学标志。淀粉样蛋白聚集体已在体外被广泛研究，并且众所周知成熟的淀粉样蛋白原纤维含有有序的平行β结构。从未聚集的肽到原纤维的结构进化可以通过显著偏离成熟原纤维的中间结构（例如反平行β-折叠）来介导。然而，目前尚不清楚这些中间结构是否存在于斑块中，这限制了从淀粉样蛋白聚集体的体外结构表征到AD的结果的翻译。这是由于无法将常见的结构生物学技术扩展到离体组织测量。在这里，我们报告使用红外（IR）成像，其中我们可以在空间上定位斑块和探测其蛋白质结构分布的分子灵敏度的IR光谱。分析AD组织中的单个斑块，我们证明纤维状淀粉样蛋白斑块表现出反平行β折叠特征，从而提供了AD脑中体外结构和淀粉样蛋白聚集体之间的直接联系。我们进一步验证了体外聚集体的红外成像结果，并表明反平行β-折叠结构是淀粉样蛋白原纤维的一个独特的结构方面。
Aggregation of amyloid β (Aβ) peptides into extracellular plaques is a hallmark of the molecular pathology of Alzheimer’s disease (AD). Amyloid aggregates have been extensively studied in vitro, and it is well-known that mature amyloid fibrils contain an ordered parallel β structure. The structural evolution from unaggregated peptide to fibrils can be mediated through intermediate structures that deviate significantly from mature fibrils, such as antiparallel β-sheets. However, it is currently unknown if these intermediate structures exist in plaques, which limits the translation of findings from in vitro structural characterizations of amyloid aggregates to AD. This arises from the inability to extend common structural biology techniques to ex vivo tissue measurements. Here we report the use of infrared (IR) imaging, wherein we can spatially localize plaques and probe their protein structural distributions with the molecular sensitivity of IR spectroscopy. Analyzing individual plaques in AD tissues, we demonstrate that fibrillar amyloid plaques exhibit antiparallel β-sheet signatures, thus providing a direct connection between in vitro structures and amyloid aggregates in the AD brain. We further validate results with IR imaging of in vitro aggregates and show that the antiparallel β-sheet structure is a distinct structural facet of amyloid fibrils.