<br>红外光谱成像揭示淀粉样蛋白β斑块中的中间反平行 β 结构,ACS Chemical Neuroscience

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红外光谱成像揭示淀粉样蛋白β斑块中的中间反平行 β 结构
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2023-10-06 , DOI: 10.1021/acschemneuro.3c00400
Brooke Holcombe ₁ , Abigail Foes ₁ , Siddhartha Banerjee ₁ , Kevin Yeh ₂ , Shih-Hsiu J Wang ₃ , Rohit Bhargava ₄ , Ayanjeet Ghosh ₁

Affiliation

淀粉样蛋白 β （Aβ）肽聚集到细胞外斑块中是阿尔茨海默病（AD）分子病理学的一个标志。淀粉样蛋白聚集体已在体外进行了广泛研究，众所周知，成熟的淀粉样蛋白原纤维包含有序的平行β结构。从未聚集的肽到原纤维的结构演变可以通过明显偏离成熟原纤维的中间结构来介导，例如反平行β片。然而，目前尚不清楚这些中间结构是否存在于斑块中，这限制了淀粉样蛋白聚集体的体外结构表征结果向 AD 的转化。这是因为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，我们报告了红外（IR）成像的使用，其中我们可以利用红外光谱的分子灵敏度在空间上定位斑块并探测其蛋白质结构分布。分析 AD 组织中的单个斑块，我们证明纤维淀粉样蛋白斑块表现出反平行的 β 片特征，从而在 AD 大脑中的体外结构和淀粉样蛋白聚集体之间提供直接联系。我们通过体外聚集体的红外成像进一步验证结果，并表明反平行β片结构是淀粉样蛋白原纤维的一个独特结构方面。

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Intermediate Antiparallel β Structure in Amyloid β Plaques Revealed by Infrared Spectroscopic Imaging

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.

更新日期：2023-10-06

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