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Nat Neurosci. 2015 Oct;18(10):1518-29. doi: 10.1038/nn.4107. Epub 2015 Sep 14.

ScaleS: an optical clearing palette for biological imaging.

Author information

Laboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.
Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-Cho, Sakyo-ku, Kyoto, Japan.
Biotechnological Optics Research Team, Center for Advanced Photonics, RIKEN, Wako-city, Saitama, Japan.
Support Unit for Animal Resources Development, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.
Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.


Optical clearing methods facilitate deep biological imaging by mitigating light scattering in situ. Multi-scale high-resolution imaging requires preservation of tissue integrity for accurate signal reconstruction. However, existing clearing reagents contain chemical components that could compromise tissue structure, preventing reproducible anatomical and fluorescence signal stability. We developed ScaleS, a sorbitol-based optical clearing method that provides stable tissue preservation for immunochemical labeling and three-dimensional (3D) signal rendering. ScaleS permitted optical reconstructions of aged and diseased brain in Alzheimer's disease models, including mapping of 3D networks of amyloid plaques, neurons and microglia, and multi-scale tracking of single plaques by successive fluorescence and electron microscopy. Human clinical samples from Alzheimer's disease patients analyzed via reversible optical re-sectioning illuminated plaque pathogenesis in the z axis. Comparative benchmarking of contemporary clearing agents showed superior signal and structure preservation by ScaleS. These findings suggest that ScaleS is a simple and reproducible method for accurate visualization of biological tissue.

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