NSRRC Users Prof. Yuh-Ju Sun and Dr. Chwan-Deng Hsiao Solved the Mystery of Brain Calcification

A research team led by the NSRRC user, Prof. Yuh-Ju Sun (Institute of Bioinformatics and Structural Biology at National Tsing Hua University) has identified the molecular mechanism of phosphate transporter, which offers a glimmer of hope for dementia treatments. Prof. Sun collaborated with another NSRRC user, Dr. Chwan-Deng Hsiao (Academia Sinica), and revealed the structure of the sodium dependent phosphate transporter. This discovery marked a significant milestone for the studies on membrane proteins, and the research result was published in the prestigious journal Science Advances in August 2020.

Read more on the NSRRC website

Image: Prof. Yuh-Ju Sun and her collaborator Dr. Chwan-Deng Hsiao solved the structure of membrane proteins, paving the way for a better treatment of dementia.

New nanoimaging method traces metal presence in Parkinson’s brain

Many neurodegenerative diseases like Parkinson’s and Alzheimer’s often exhibit an excess of iron in the brain. Scientists have developed a method to trace the presence of metals in brain at the sub-cellular level, particularly in organelles of neurons vulnerable to these diseases. The results are published in Communications Biology.

The level and distribution of iron in the brain normally contributes to essential cellular functions, including mitochondrial respiration, via its capability to transfer electrons. In vulnerable populations of neurons however, iron dysregulation can have detrimental effects. Genetic defects affecting iron metabolism cause brain diseases, including Parkinson’s and Alzheimer’s, both associated with iron overload. “It is important to be able to explore metal distribution in neurons and glia (non-neuronal cells), with the aim to identify potential causal mechanisms in neurodegeneration”, explains Bernard Schneider, scientist at EPFL and co-author of the study.

Until now, there was no method that could trace the elements with sensitivity and nanometre resolution. A team of scientists from LGL-TPE (Laboratoire de Géologie de Lyon : Terre, Planètes et Environnement), Institut des Sciences de la terre (ISTerre) de Grenoble, the ESRF and the EPFL (École Polytechnique Fédérale de Lausanne) have now combined the techniques of transmission electron microscopy and synchrotron X-ray fluorescence at the ESRF in order to evaluate the element unbalance in Parkinson’s disease.

Read more on the ESRF website

Image : Composition of P/Fe/S in a section of a neuron of the substantia nigra. The neuron and its nucleus are highlighted by dashed lines. Cytoplasmic granules rich in Fe and S are pointed out by arrows. 

Credit: Lemelle, L, et al, Communications Biology, DOI : 10.1038/s42003-020-1084-0.

Lucy had an ape-like brain, but prolonged brain growth like humans

A study led by the Max Planck Institute for Evolutionary Anthropology reveals that Lucy’s species, Australopithecus afarensis, had an ape-like brain.

However, the protracted brain growth suggests that infants may have had a long dependence on caregivers, as in humans. The study, in collaboration with the ESRF, is published in Science Advances.

The species Australopithecus afarensis, well-known as Lucy’s species, inhabited East Africa more than three million years ago, and occupies a key position in the hominin family tree.. “Lucy and her kind provide important evidence about early hominin behavior. They walked upright, had brains that were around 20 percent larger than those of chimpanzees and may have used sharp stone tools,” explains senior author Zeresenay Alemseged from the University of Chicago, who directs the Dikika field project in Ethiopia, where the skeleton of an Australopithecus afarensis child, known as Dikika child and nicknamed Selam, was found in the year 2000. “Our new results show how their brains developed, and how they were organized,” adds Alemseged.

>Read more on the European Synchrotron website

Image: Brain imprints in fossil skulls of the speciesAustralopithecus afarensis(famous for “Lucy” and the “Dikika child” from Ethiopia pictured here) shed new lighton the evolution of brain growth and organization. The exceptionally preservedendocranial imprint of the Dikika child reveals an ape-likebrain organization, and nofeatures derived towards humans.
Credit: Philipp Gunz, MPI EVA Leipzig.

Synchrotron light unveils new insights about amytrophic lateral sclerosis

Synergetic combination of different imaging and spectroscopic synchrotron techniques performed in ALBA and APS (USA) has discovered new aspects about astrocytes cells of this neurodegenerative disease.

Results, published in Analytical Chemistry, show significant differences between ALS and control astrocytes, including structural, chemical and macromolecular anomalies. Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that causes the degeneration and death of neurons that control voluntary muscles. Still today the causes of this disease are unknown in 90% of the cases. However, some of them are caused by the mutation of sod1 gene. This gene encodes an enzyme (SOD1) that is involved in cellular protection against oxidative stress. Mutations dramatically alter the biochemical properties of SOD1, in particular its metal binding affinity and its anti-oxidative activity levels. But it is still unknown how these mutations block the normal cell function and lead to death of motor neurons. The ALBA Synchrotron, in collaboration with researchers from the University of Belgrade Pavle Andjus and Stefan Stamenković (who accomplished his PhD thesis using these results) and Vladan Lučić from Max Planck Institute of Biochemistry (Germany), has studied with synchrotron light techniques and classical biochemical laboratory approaches the cellular structural and biochemical changes of this gene mutation in a transgenic animal model of ALS. In particular, scientists have analysed astrocytes, one kind of brain cells that are key players in pathological processes of this disease.

>Read more on the ALBA website

Image: Researcher Tanja Dučić during the experiment performed at ALBA, at the MIRAS beamline.

A new approach for finding Alzheimer’s treatments

Considering what little progress has been made finding drugs to treat Alzheimer’s disease, Maikel Rheinstädter decided to come at the problem from a totally different angle—perhaps the solution lay not with the peptide clusters known as senile plaques typically found in the brains of Alzheimer’s patients, but with the surrounding brain tissue that allowed those plaques to form in the first place.
It was a novel approach that paid off for Rheinstädter and his team of researchers from McMaster University who used the Canadian Light Source in Saskatoon as part of a study of the effect various compounds have on membranes in brain tissue and the possible impact on plaque formation.

“Alzheimer’s disease has interested me for a long time,” said Rheinstädter, a professor in the Department of Physics and Astronomy and the Origins Institute at McMaster. “It is something almost every Canadian will be affected by in their lives.”

>Read more on the Canadian Light Source website

Image: Adam Hitchcock, Adree Khondker and Maikel Rheinstädter.

Unprecedented 3D images of neurons in healthy and epileptic brains

Results open new perspectives for the study of neurodevelopment and neurodegenerative diseases.

A comprehensive understanding of the brain, its development, and eventual degeneration, depends on the assessment of neuronal number, spatial organization, and connectivity. However, the study of the brain architecture at the level of individual cells is still a major challenge in neuroscience.
In this context, Matheus de Castro Fonseca, from the Brazilian Biosciences National Laboratory (LNBio), and collaborators [1] used the facilities of the Brazilian Synchrotron Light Laboratory (LNLS) to obtain, for the first time, three-dimensional images in high resolution of part of the neuronal circuit, observed directly in the brain and with single cell resolution.

The researchers used the IMX X-Ray Microtomography beamline, in combination with the Golgi-Cox mercury-based impregnation protocol, which proved to be an efficient non-destructive tool for the study of the nervous system. The combination made it possible to observe the points of connectivity and the detailed morphology of a region of the brain, without the need for tissue slicing or clearing.
The mapping of neurons in healthy and unhealthy tissues should improve the research in neurodegenerative and neurodevelopmental diseases. As an example of this possibility, the work presents, for the first time in 3D, the neuronal death in an animal model of epilepsy.

The researchers are now working to extend the technique to animal models of Parkinson’s disease. The intention is to better understand the cellular mechanisms involved in the onset and progression of the disease. In the future, with the inauguration of the new Brazilian synchrotron light source, Sirius, the researchers believe that it will be possible to obtain images at the subcellular level, that is, images of the interior of the neurons.

>Read more on the Brazilian Synchrotron Light Laboratory website

Image: X-ray microtomography of the cerebral cortex showing the segmentation of individual neurons. Each color represents a single neuron or a group of neurons.

Google Maps for the cerebellum

A team of researchers from Göttingen has successfully applied a special variant of X-ray imaging to brain tissue. With the combination of high-resolution measurements at DESY’s X-ray light source PETRA III and data from a laboratory X-ray source, Tim Salditt’s group from the Institute of X-ray Physics at the Georg August University of Göttingen was able to visualize about 1.8 million nerve cells in the cerebellar cortex. The researchers describe the investigations with the so-called phase contrast tomography in the Proceedings of the National Academy of Sciences (PNAS).
The human cerebellum contains about 80 percent of all nerve cells in 10 percent of the brain volume – one cubic millimeter can therefore contain more than one million nerve cells. These process signals that mainly control learned and unconscious movement sequences. However, their exact positions and neighbourhood relationships are largely unknown. “Tomography in the so-called phase contrast mode and subsequent automated image processing enables the cells to be located and displayed in their exact position,” explains Mareike Töpperwien from the Institute of X-ray Physics at the University of Göttingen, lead author of the publication.

>Read more on the PETRA III at DESY website

Image: Result of the phase contrast X-ray tomography at DESY’s X-ray source PETRA III.
Credit: Töpperwien et al., Universität Göttingen

Metallic drivers of Alzheimer’s disease

The detection of iron and calcium compounds in amyloid plaque cores

X-ray spectromicroscopy at the Scanning X-ray Microscopy beamline (I08), here at Diamond, has been utilised to pinpoint chemically reduced iron and calcium compounds within protein plaques derived from brains of Alzheimer’s disease patients. The study, published in Nanoscale, has shed light on the way in which metallic species contribute to the pathogenesis of Alzheimer’s disease and could help direct future therapies.

Alzheimer’s disease is a neurodegenerative disease that is associated with dementia and shortened life expectancy. The disease is characterised by the formation of protein plaques and tangles in the brain that impair function. As well as protein plaques, perturbed metal ion homeostasis is also linked with pathogenesis, and iron levels in particular are elevated in certain regions of the brain.

A team of scientists with a long history in exploring biomineralisation in Alzheimer’s brains set out to characterise the iron species that are associated with the amyloid protein plaques. They extracted samples from the brains of two deceased patients who had Alzheimer’s and applied synchrotron X-ray spectromicroscopy to differentiate the iron oxide phases in the samples.

They noted evidence that the chemical reduction of iron, and indeed the formation of a magnetic iron oxide called magnetite, which is not commonly found in the human brain, had occurred during amyloid plaque formation, a finding that could help inform the outcomes of future Alzheimer’s therapies.

>Read more on the Diamond Light Source website

Image: Synchrotron soft X-ray nano-imaging and spectromicroscopy reveals iron and calcium biomineralisation in Alzheimer’s disease amyloid plaques.

The Brain Revisited

How does it work? Mazes of neurons all joined together by trillions of synaptic connections…

Everything we do – from writing our name to remembering it – is the result of billions of nerve cells, also known as neurons, firing electro-chemical signals through our brains. The way we experience the world around us is tied up in these mazes of neurons, all joined together by trillions of synaptic connections. Thanks to all this processing power, our brains are more complex than any computer system on earth.

The astonishing intricacy of our brains allows us to perform incredible feats of thought. But there’s also a downside to possessing all this brain power. With all that complex machinery at play, errors in the system can spell big trouble for our health. Neurodegenerative conditions like Parkinson’s and Alzheimer’s are linked to problems with the brain’s neural network. Because these networks are so labyrinthine, we don’t yet understand the brain and, in turn, how to combat neurological conditions, as well as we’d like.