Yin Xianzhen, Zhang Xiaochuan, Zhang Jingjing, Yang Weicheng, Sun Xian, Zhang Haiyan, Gao Zhaobing, Jiang Hualiang
Center for MOST and Image Fusion Analysis, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Front Neurosci. 2022 Apr 19;16:870520. doi: 10.3389/fnins.2022.870520. eCollection 2022.
Simultaneously visualizing Amyloid-β (Aβ) plaque with its surrounding brain structures at the subcellular level in the intact brain is essential for understanding the complex pathology of Alzheimer's disease, but is still rarely achieved due to the technical limitations. Combining the micro-optical sectioning tomography (MOST) system, whole-brain Nissl staining, and customized image processing workflow, we generated a whole-brain panorama of Alzheimer's disease mice without specific labeling. The workflow employed the steps that include virtual channel splitting, feature enhancement, iso-surface rendering, direct volume rendering, and feature fusion to extract and reconstruct the different signals with distinct gray values and morphologies. Taking advantage of this workflow, we found that the denser-distribution areas of Aβ plaques appeared with relatively more somata and smaller vessels, but show a dissimilar distributing pattern with nerve tracts. In addition, the entorhinal cortex and adjacent subiculum regions present the highest density and biggest diameter of plaques. The neuronal processes in the vicinity of these Aβ plaques showed significant structural alternation such as bending or abrupt branch ending. The capillaries inside or adjacent to the plaques were observed with abundant distorted micro-vessels and abrupt ending. Depicting Aβ plaques, somata, nerve processes and tracts, and blood vessels simultaneously, this panorama enables us for the first time, to analyze how the Aβ plaques interact with capillaries, somata, and processes at a submicron resolution of 3D whole-brain scale, which reveals potential pathological effects of Aβ plaques from a new cross-scale view. Our approach opens a door to routine systematic studies of complex interactions among brain components in mouse models of Alzheimer's disease.
在完整大脑的亚细胞水平上同时可视化淀粉样β蛋白（Aβ）斑块及其周围的脑结构对于理解阿尔茨海默病的复杂病理至关重要，但由于技术限制，这一目标仍很少实现。我们结合微光学切片断层扫描（MOST）系统、全脑尼氏染色和定制的图像处理工作流程，生成了未进行特异性标记的阿尔茨海默病小鼠全脑全景图。该工作流程采用了包括虚拟通道分割、特征增强、等值面渲染、直接体绘制和特征融合等步骤，以提取和重建具有不同灰度值和形态的不同信号。利用这一工作流程，我们发现Aβ斑块分布较密集的区域出现了相对更多的体细胞和更小的血管，但与神经束呈现出不同的分布模式。此外，内嗅皮质和相邻的海马下托区域呈现出最高的斑块密度和最大的斑块直径。这些Aβ斑块附近的神经元突起显示出明显的结构改变，如弯曲或突然分支终止。在斑块内部或附近观察到的毛细血管有大量扭曲的微血管和突然终止的情况。这一全景图同时描绘了Aβ斑块、体细胞、神经突起和神经束以及血管，使我们首次能够在三维全脑尺度的亚微米分辨率下分析Aβ斑块如何与毛细血管、体细胞和突起相互作用，这从一个新的跨尺度视角揭示了Aβ斑块的潜在病理效应。我们的方法为在阿尔茨海默病小鼠模型中对脑成分之间复杂相互作用进行常规系统研究打开了一扇门。
