Tracking individual carbon atoms deep into the brain’s neurons

Using a geologist’s imaging tool, researchers have made unprecedented high-resolution images of how carbon atoms from glucose are integrated into brain cells, providing new insight and opening new doors into the fate of glucose in the brain.

Glucose – a form of sugar – fuels the brain. But how it goes from the blood to the brain cells and where it ultimately winds up are not yet well understood. Harnessing the power of a special kind of microscope that was used for the first time to image metabolism of the brain, researchers from EPFL, the Nestlé Health Institute, and the University of Lausanne have tracked the fate of individual carbon atoms deep into the brain’s neurons and astrocytes. Their work, published in the Journal of Chemical Neuroanatomy, paves the way for a better understanding of how healthy and diseased brains metabolize glucose, which in the future could contribute to the development of new methods to diagnose and treat neurological diseases.

“Half of the glucose we have in our blood is consumed by our brain; this we know. But what we don’t know, at least not in detail, is what this glucose is used for and where it winds up,” says Arnaud Comment, one of the study’s lead investigators. The reason for this is that existing experimental methods have been unable to conclusively resolve this question. But thanks to a microscope originally developed to study the isotopic composition of rock samples called a NanoSIMS, it looks like researchers may finally have a tool to help them find an answer.

“The NanoSIMS gives us a view of what goes on at the sub-cellular level that nobody has had access to before. It is an example of a geochemical technology that is being pushed into the realm of life sciences through a cross-campus collaboration,” says Meibom, whose EPFL research lab runs the NanoSIMS, the only one of its kind in Switzerland. Combining transmission electron microscopy (TEM) with secondary ion mass spectroscopy, the device lets researchers locate trace amounts of labeled atoms down to a resolution of only a few hundred nanometers.

“In this study, we imaged the fate of glucose, the brain’s main energy source, at the cellular level,” says Meibom, who is also the study’s second lead investigator. “Our question was: where is the brain putting its money? We do not have an answer quite yet, but we do have data showing that after a few hours, neurons have accumulated more carbon from the glucose in their structure than astrocytes. We can find high concentrations of carbon atoms from the glucose in the neurons’ nuclei and other cellular compartments – a sign of increased metabolic activity.”

While their findings neither refute nor validate current theory holding that astrocytes extract glucose from the blood stream and deliver some of it to neurons, they provide an unprecedented and very accurate snapshot into exactly where the carbon from the glucose is going in the brain.

But, the researchers hope, their method could help determine the early metabolic signature of certain types of disease, which could be a boon to research and the development of treatment strategies. Catching the onset of Alzheimer’s, for example, is complicated by the fact that, by the time the structure of the brain’s cells is visibly affected, it is already too late. Instead, more subtle cues would have to be picked up, such as changes to the cells’ metabolism – the chemical reactions that sustain them, providing them with energy and matter. Changes in glucose metabolism of specific parts of the brain could, for example, provide an early warning for the onset of Alzheimer’s.

Today, the NanoSIMS lets researchers study the incorporation of labeled atoms into solid structures, but Meibom wants to take it one step further. “We are working on extending the capabilities of the NanoSIMS to be able to work with frozen samples, giving us a means of visualizing soluble compounds as well. Using such a CryoNanoSIMS, we will not only be able to see where specific compounds have been integrated into the proteins that make up the cell, but we will also be able to trace their dissolved metabolite precursors,” he says.

Reference: Yuhei Takado et al. Imaging the time-integrated cerebral metabolic activity with subcellular resolution through nanometer-scale detection of biosynthetic products deriving from 13C-glucose, Journal of Chemical Neuroanatomy, Available online 25 September 2015,

EPFL

Alzheimer-substance may be the nanomaterial of tomorrow

It causes brain diseases like Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob’s disease. It is also hard and rigid as steel. Now research at Chalmers University of Technology shows that the amyloid protein carries unique characteristics that may lead to the development of new composite materials for nano processors and data storage of tomorrow and even make objects invisible.

Piotr Hanczyc, PhD student at the department of Chemical and Biological Engineering, shows in an article in Nature Photonics, that the amyloid, a very dense aggregate of protein that causes brain diseases like Alzheimer's and Parkinson's, carries unique characteristics. Unlike well-functioning protein the amyloid reacts upon multi photon laser irradiation. This laser may in the future possibly be used for detection of amyloids inside a human brain. This discovery is in itself a breakthrough.

- But you can also create these aggregates in an artificial way in a laboratory and in combination with other materials create unique characteristics, Piotr Hanczyc says.

The amyloid aggregates are as hard and rigid as steel. The difference is that steel is much heavier and has defined material properties whereas amyloids can be tuned for desired purpose. By attaching a material’s molecules to the dense amyloid its characteristics change. This has been known for more than ten years and is already used by scientists.

- What hasn’t been known is that the amyloids react to multi-photon irradiation and this opens up new possibilities to also change the nature of the material attached to the amyloids, Piotr Hanczyc says.

The amyloids are shaped like discs densely piled upon each other.  When a material gets merged with these discs its molecules end up so densely and regularly that they can communicate and exchange information. This means totally new possibilities to change a material’s characteristics. 

Multi-photon tests on materials tied to amyloids are yet to be performed, but Piotr sees an opportunity for cooperation with Chalmers material science researchers interested for example in solar cell technology. 

And though it may still be science fiction, he also considers that one day scientists may use the material properties of amyloid fibrils in the research of invisible metamaterials.

- An object’s ability to reflect light could be altered so that what’s behind it gets reflected instead of the object itself, in principle changing the index of light refraction, kind of like when light hits the surface of water, Piotr Hanczyc says. 

Source: http://www.chalmers.se/en/departments/chem/news/Pages/Alzheimer-substance-may-be-the-nanomaterial-of-tomorrow.aspx

Cell auto-cleaning mechanism mediates the formation of plaques in Alzheimer’s

Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer’s disease. It might be a potential drug target for the treatment of the disease, concludes new research from the RIKEN Brain Science Institute in Japan. The study sheds light on the metabolism of amyloid beta, and its role in neurodegeneration and memory loss.

The role of autophagy in Aβ secretion from neurons

In a study published today in the journal Cell Reports, Drs. Per Nilsson, Takaomi Saido and their team show for the first time using transgenic mice that a lack of autophagy in neurons prevents the secretion of amyloid beta and the formation of amyloid beta plaques in the brain. The study also reveals that an accumulation of amyloid beta inside neurons is toxic for the cells.

Alzheimer’s disease, the most common form of dementia, affects nearly 36 million people worldwide, and this number is set to double over the next 20 years. However, the causes of the disease are not well understood and no disease-modifying treatment is available today.

Patients with Alzheimer’s disease have elevated levels of the peptide amyloid beta in their brain and amyloid beta plaques form outside their neurons. This accumulation of amyloid beta causes the neurons to die, but until now the underlying mechanism remained a mystery. And whether the elevated levels of the peptide inside or outside the cells are to blame was unknown.

Autophagy is a cellular cleaning mechanism that normally clears any protein aggregates or other ‘trash’ within the cells, but that is somewhat disturbed in Alzheimer’s patients.

To investigate the role of autophagy in amyloid beta metabolism, Nilsson et al. deleted an important gene for autophagy, Atg7, in a mouse model of Alzheimer’s disease. Contrary to what they were expecting, their results showed that a complete lack of autophagy within neurons prevents the formation of amyloid beta plaque around/outside the cells. Instead, the peptide accumulates inside the neurons, where it causes neuronal death, which in turn leads to memory loss.

“Our study explains how amyloid beta is secreted from the neurons, via autophagy, which wasn’t well understood,” comments Dr Nilsson. “To control amyloid beta metabolism including its secretion is a key to control the disease. Autophagy might therefore be a potential drug target for the treatment of Alzheimer’s disease,” he adds.

Source: http://www.riken.jp/en/pr/press/2013/20131004_1/