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X-ray vision – new method to examine Alzheimer’s disease brain samples

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Posted September 16, 2015

Superman has an x-ray vision – we all know that. And a lot of us dreamed to have such powers ourselves. However, such ability is much more useful to scientists that superheroes and now they found a way to turn it into a reality. Researchers at the RIKEN Brain Science Institute in Japan created a way to illuminate 3D brain anatomy at very high resolutions using a new transparent tissue. This discovery may help researching and treating such diseases as Alzheimer’s.

3D visualization of “diffuse” plaques, created using ScaleS technology. This technology already helped scientists to make few discoveries and has demonstrated many advantages over current 2D imaging. Image credit: riken.jp

3D visualization of “diffuse” plaques, created using ScaleS technology. This technology already helped scientists to make few discoveries and has demonstrated many advantages over current 2D imaging. Image credit: riken.jp

It is hard to overrate discoveries like this, although it is not easy to explain it to a common public. Lead scientists of the research, Atsushi Miyawaki, explained: “The usefulness of optical clearing techniques can be measured by their ability to gather accurate 3D structural information that cannot be readily achieved through traditional 2D methods. Here, we achieved this goal using a new procedure, and collected data that may resolve several current issues regarding the pathology of Alzheimer’s disease”. He also jokingly added – “While Superman’s x-ray vision is only the stuff of comics, our method, called ScaleS, is a real and practical way to see through brain and body tissue.”

Generating see-through tissue (a process called optical clearing) was a goal for many scientists recently, because this technology, combined with advanced microscopy imaging techniques, could help analysing complex structural details of our bodies, organs, and cells—both healthy and diseased.

All existing methods to do so were not ideal, because they could damage the structures under study. RIKEN scientists developed a new method, called Scale, back in 2011 and it suffered from the same problem – the transparency process itself could damage the structures. However, now they think they overcame main obstacles and developed a method with many practical applications, called ScaleS.

Scale was an aqueous solution based on urea. Now scientists say that the main ingredient allowing this method to avoid usual drawbacks is sorbitol, a common sugar alcohol. Results are incredible – by combining sorbitol with urea at right proportions, scientists could create transparent brains with minimal tissue damage. This method works with florescent and immunohistochemical labelling techniques and could even be applied to older animals. Created transparent brain samples can be stored in ScaleS solution for more than a year without damage. Important internal structures remain intact and brain is still firm enough to be cut to micron-thick slices.

Scientists note that microscopy is an important challenge as well. Transparent brain tissue must be viewable by both light and electron microscopy.  And ScaleS managed this task with grace – it provides an optimal combination of cleared tissue and fluorescent signals, which allows tissues to be viewed in both kinds of microscopy. Furthermore, scientists say the quality and preservation of cellular structures viewed by electron microscopy is unparalleled.

Scientists created several variations of this method that can be combined to achieve desired results. For example, by combining ScaleS with AbScale (a variation for immunolabelling) and ChemScale (a variation for fluorescent chemical compounds), scientists managed to achieve multi-colour high-resolution 3D images of amyloid beta plaques in older mice from a genetic mouse model of Alzheimer’s disease. Then scientists put new technology to its practical application.

There are mysterious “diffuse” plaques seen in the post-mortem brains of Alzheimer’s disease patients that are typically undetectable using 2D imaging. Therefore, scientists tried to visualize these plaques in 3D using ScaleS. This gave scientists some new information about these plaques – it turns out that they are not isolated, but have extensive association with microglia (mobile cells that surround and protect neurons) instead.

Scientists found a different application for ScaleS too. They examined the 3D positions of active microglial cells and amyloid beta plaques. Although many scientists suggested that active microglial cells are located near plaques, this 3D analysis showed that association with active microglial cells occurs early in plaque development, but not in later stages of the disease after the plaques have already accumulated.

Scientists are certain that ScaleS have many advantages over current 2D imaging technologies. Furthermore, it can be used to research other brain diseases as well, not only Alzheimer’s. It provides that kind of x-ray vision we really needed, seeking to reach a breakthrough in treating major brain diseases.

Source: RIKEN

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