State Key Laboratory of Surface Physics and Department of Physics, Multiscale Research Institute of Complex Systems, Human Phenome Institute, Key Laboratory of Micro and Nano Photonics Structures (Ministry of Education), Fudan University, Shanghai 200433, China.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Sci Adv. 2018 Nov 16;4(11):eaat7715. doi: 10.1126/sciadv.aat7715. eCollection 2018 Nov.
One of the key pathological features of Alzheimer's disease (AD) is the existence of extracellular deposition of amyloid plaques formed with misfolded amyloid-β (Aβ). The conformational change of proteins leads to enriched contents of β sheets, resulting in remarkable changes of vibrational spectra, especially the spectral shifts of the amide I mode. Here, we applied stimulated Raman scattering (SRS) microscopy to image amyloid plaques in the brain tissue of an AD mouse model. We have demonstrated the capability of SRS microscopy as a rapid, label-free imaging modality to differentiate misfolded from normal proteins based on the blue shift (~10 cm) of amide I SRS spectra. Furthermore, SRS imaging of Aβ plaques was verified by antibody staining of frozen thin sections and fluorescence imaging of fresh tissues. Our method may provide a new approach for studies of AD pathology, as well as other neurodegenerative diseases associated with protein misfolding.
阿尔茨海默病（AD）的一个关键病理学特征是存在由错误折叠的淀粉样-β（Aβ）形成的细胞外淀粉样斑块沉积。蛋白质构象的改变导致β片层含量增加，从而导致振动光谱发生显著变化，特别是酰胺 I 模式的光谱位移。在这里，我们应用受激拉曼散射（SRS）显微镜来对 AD 小鼠模型脑组织中的淀粉样斑块进行成像。我们已经证明了 SRS 显微镜作为一种快速、无标记的成像方式的能力，它可以根据酰胺 I SRS 光谱的蓝移（约 10 cm）来区分错误折叠的蛋白质与正常蛋白质。此外，我们通过对冷冻薄片进行抗体染色和对新鲜组织进行荧光成像来验证了 Aβ斑块的 SRS 成像。我们的方法可能为 AD 病理学以及其他与蛋白质错误折叠相关的神经退行性疾病的研究提供新的途径。
