Tag: Alzheimer’s

X-rays bring high-resolution brain mapping within reach

X-rays bring high-resolution brain mapping within reach

Scientists at the Swiss Light Source SLS have succeeded in mapping a piece of brain tissue in 3D at unprecedented resolution using X-rays – non-destructively. The breakthrough overcomes a long-standing technological barrier that had limited the use of X-rays for such studies. With the SLS upgrade now complete, the path lies open to imaging much larger samples of brain tissue at high resolution – and to gaining new understanding of its complex architecture. The study, a collaboration between Paul Scherrer Institute PSI and the Francis Crick Institute in the UK, is published in Nature Methods.

“The brain is one of the most complex biological systems in the world,” says Adrian Wanner, who leads the Structural Neurobiology research group at Paul Scherrer Institute PSI. How neurons are wired together is what his group are trying to unravel – a field known as connectomics. 

He explains: “Take the liver: we know of about 40 cell types. We know how they are arranged. We know their functions. This is not true for the brain. And so, one could ask, what is the difference between the brain and the liver? If we look at a cell body in the brain and the liver, it’s not easy to distinguish the two. They both have a nucleus, an endoplasmic reticulum – they both have the same intercellular machinery, the same molecules, the same types of proteins. This is not the difference. What is really different is how the brain cells are organised and connected.”

Read more on the PSI website

Image: One cubic millimetre of brain tissue contains about 100 000 neurons, connected through some 700 million synapses and 4 kilometres of ‘cabling’. This complex 3D wiring underlies brain function – yet is extraordinarily difficult to study.

Credit: © Adobe Stock

How the cheese-noodle principle could help counter Alzheimer’s

How the cheese-noodle principle could help counter Alzheimer’s

Researchers at the Paul Scherrer Institute PSI have clarified how spermine – a small molecule that regulates many processes in the body’s cells – can guard against diseases such as Alzheimer’s and Parkinson’s: it renders certain proteins harmless by acting a bit like cheese on noodles, making them clump together. This discovery could help combat such diseases. The study has now been published in the journal Nature Communications.

Our life expectancy keeps rising – and as it does, age-related illnesses, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s, become increasingly common. These diseases are caused by accumulations in the brain of harmful protein structures consisting of incorrectly folded amyloid proteins. Their shape is reminiscent of fibres or spaghetti. To date, there is no effective therapy to prevent or eliminate such accumulations.

Yet a naturally occurring molecule in the body called spermine offers hope. In experiments, researchers led by study leader Jinghui Luo, in the Center for Life Sciences at the Paul Scherrer Institute PSI, have discovered that this substance is capable of extending the life span of small nematode worms, improving their mobility in old age, and strengthening the powerhouses of their cells – the mitochondria. Specifically, the researchers observed how spermine helps the body’s immune system eliminate nerve-damaging accumulations of amyloid proteins. 

The new findings could serve as a basis for developing novel therapies for such diseases.

A central mediator of cellular processes

Spermine is a vital substance for the organism. It belongs to the so-called polyamines, which are relatively small organic molecules. Spermine, first discovered more than 150 years ago, is named after the seminal fluid, as it is found in particularly high concentrations there. But it also occurs in many other cells of the body – especially those that are active and capable of dividing.

Spermine promotes cell mobility and activity and controls numerous processes. Above all, it interacts with the nucleic acids of the genome, regulating the expression of genes and their conversion into proteins. This ensures that cells can properly grow and divide and ultimately die. Spermine is also central to an important cellular process called biomolecular condensation: In this process, certain macromolecules, such as proteins and nucleic acids, segregate and collect within the cell in a droplet-like form, so that important reactions can take place there.

In connection with neurodegenerative diseases such as Alzheimer’s or Parkinson’s, there has previously been evidence that spermine can protect nerve cells and alleviate age-related memory loss. Lacking until now, however, has been a more precise understanding of how spermine intervenes in nerve-damaging processes – understanding that might make it possible to derive medical benefits from it.

Assisting cellular waste removal

Jinghui Luo’s group has now investigated this in more detail. In addition to optical microscopy, the researchers also used the SAXS scattering technique at PSI’s Swiss Light Source SLS to shed light on the molecular dynamics of these processes. The investigations were conducted both in a glass capillary (in vitro) and in a living organism (in vivo). The nematode C. elegans served as a model organism.

Read more on the PSI website

Image: Jinghui Luo is a researcher at the Center for Life Sciences at the Paul Scherrer Institute PSI. He studies accumulations of so-called amyloid proteins, which lead to nerve damage in the brain. His research aims to help mitigate neurodegenerative diseases such as Alzheimer’s and Parkinson’s in the long term.

Credit: © Paul Scherrer Institute PSI/Markus Fischer

New insights into what happens in cells in early Alzheimer’s

New insights into what happens in cells in early Alzheimer’s

Researchers led by the ESRF, the European Synchrotron, have found that amyloid oligomers play a role in speeding up mitochondrial energetics during the early stages of Alzheimer’s, in contrast to what has been previously found in more advanced Alzheimer’s brain tissues.

The origin of Alzheimer’s disease, which affects 30 million people worldwide, is still not clear despite an international research effort and significant progress in research. And yet, identifying the factors driving this incurable neurodegenerative disease is essential to find better ways to diagnose Alzheimer, delay its onset and prevent progression. “Before understanding the pathology, we need to understand the biology”, explains Montse Soler López, head of the Structural Biology group at the ESRF and co-corresponding author of the study.

Alzheimer’s is an incurable disease that normally appears after the age of 65. However, changes in the brain begin 20 years before the disease appears. “We believe that malfunctioning of the mitochondria can take place 20 years before the person shows symptoms of the disease”, explains Soler López. For a long time, researchers have focused on the amyloid plaques in the brain as the potential cause of the disease. However, this hypothesis is currently being reconsidered.

Now Soler López’s team, together with scientist Irina Gutsche at the Institut de Biologie Structurale (CNRS, CEA, Université Grenoble Alpes) and researchers at the EMBL, conduct a new line of research focusing on aging factors, such as mitochondrial dysfunction. Mitochondria are often referred to as the “powerhouse of cell” because of their essential role in energy production. Over time, mitochondria suffer oxidative stress and this leads to their malfunction. A recent finding indicates that individuals with Alzheimer’s may exhibit an accumulation of amyloids within mitochondria, challenging the previously belief that amyloids were solely present outside neurons.

Read more on the ESRF website

Examining individual neurons from different perspectives

Examining individual neurons from different perspectives

Correlative imaging of a single neuronal cell opens the door to profound multi-perspective sub-cellular examinations

Scientists combined two nano-imaging techniques that stand at opposite ends of the electromagnetic spectrum to demonstrate the benefits of correlative imaging to examine individual neurons from different perspectives.

To showcase this, they studied the molecular structures of amyloid proteins and investigated the role metal ions may play in the development of Alzheimer’s Disease at a previously never achieved resolution. Their detailed observations at the sub-cellular level underscore the potential of using combined nanospectroscopic tools to deal with uncertainties due to the complex nature of a biological sample.

Alzheimer’s Disease is the most common cause of dementia. Many research groups are working to reveal molecular mechanisms to better understand the process by which the disease evolves. Due to the current lack of effective treatments that could stop or prevent Alzheimer’s Disease, new approaches are necessary to find out how people can age without memory loss.

High-resolution microscopy techniques such as electron microscopy and immunofluorescence microscopy are most often used to detect amyloidogenic protein molecules, often considered key factors in the disease’s evolution. However, these commonly used methods generally lack the sensitivity necessary to depict molecular structures. This is why scientists from Lund University in collaboration with SOLEIL and MAX IV carried out a proof of concept study which showcases that combining two imaging modalities can be used as effective tools to assess structural and chemical information directly within a single cell.

Read more on the MAX IV website

Image: a O-PTIR setup: a pulsed, tunable IR laser is guided onto the sample surface (1). b X-ray fluorescence nanoimaging of individual neuronal cells deposited on Si3N4 (1). c Conceptualization of the data analysis based on superimposed optical, O-PTIR, and S-XRF images.

How a very “sociable” protein can hold clues about Alzheimer’s origin

How a very “sociable” protein can hold clues about Alzheimer’s origin

The origin of the most prevalent form of Alzheimer’s disease, which accounts for 95% of cases, is still not clear despite decades of scientific studies. “Before understanding the pathology, we need to understand the biology”, explains Montse Soler López, scientist leading research on Alzheimer’s disease at the ESRF. “The only thing we are sure about is that the most common form of Alzheimer’s is linked with ageing”, she asserts.

So researchers have been focusing on parts of the body that degrade dramatically with age. Neurons, for example, are long-lived cells, meaning that they don’t renew themselves like other cells do. Neurons lodge mitochondria, which are so-called the “powerhouse of cell” because of their active role generating energy in the body. With time, mitochondria suffer oxidative stress and this leads to their malfunction. It has been recently discovered that people with Alzheimer’s may have an accumulation of amyloids inside mitochondria (previously it was thought amyloids were only outside the neurons). Montse Soler López is trying to find whether there is a link between mitochondrial dysfunction, presence of amyloids and early disease symptoms. “We believe that malfunctioning of the mitochondria can take place 20 years before the person shows symptoms of the disease”.

Read more on the ESRF website

A new approach for finding Alzheimer’s treatments

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.

Analysing Alzheimer’s mechanisms with synchrotron light

Analysing Alzheimer’s mechanisms with synchrotron light

Researchers from the ALBA Synchrotron and the Universitat Autònoma de Barcelona (UAB) have analysed with synchrotron light different Alzheimer’s aggregates, their location and their effect in cultivated neuronal cells.

Results, published in Analytical Chemistry, pave the way to better understand the development of this disease that affects more than 30 million people worldwide.

Memory loss, communications’ difficulties, personality and behaviour changes, orientation problems … Unfortunately, these symptoms are widespread in our society, since 30 million people worldwide and 1.5 in Spain suffer from the effects of Alzheimer’s, according to the World Health Organization (WHO) and the Spanish Confederation of Family Members of Alzheimer’s and other dementias patients (CEAFA), respectively. Alzheimer’s is the most important cause of dementia and is described as a multifactorial disease that leads to neuronal cell death. Nowadays, there is no effective treatment to fight against or to prevent it.

When a person has Alzheimer’s, amyloid plaques are generated inside his brain. They are made of deposits or aggregates of the amyloid beta peptide. This peptide – which comes from a protein that is necessary for cellular functioning – tends to be aggregated by adopting different sizes and morphologies, depending on the physical and chemical conditions around it. Although it is already known that the presence of the beta amyloid peptide, together with other factors such as oxidative stress, play a key role in the onset and development of the Alzheimer’s disease, it is not still clear what causes the disease and what the consequences are.

>Read more on the ALBA website

Combined imaging approach characterises plaques associated with Alzheimer’s disease

Combined imaging approach characterises plaques associated with Alzheimer’s disease

Australian Synchrotron X-ray and infrared imaging techniques have been used in a powerful combined approach to characterise the composition of amyloid plaques that are associated with Alzheimer’s disease.

Alzheimer’s disease is major international health problem that accounts for 50-75 per cent of all cases of dementia in Australia. More than 400,000 Australians are living with dementia and it is the second leading cause of death.

Amyloid plaques are complex protein fragments which accumulate between nerve cells in the brain and may destroy connections between them, and are hallmarks of Alzheimer’s disease.

“However, it is still not known if the plaques cause Alzheimer’s or whether the Alzheimer’s causes their formation, which is why we need to improve our understanding of protein structures within plaques, and the molecular and elemental composition of tissue surrounding the plaques“ said Dr Mark Hackett of Curtin University, who led the research.

The study was published earlier in the year in Biochemistry.

As very few methods provide sufficient chemical information to study the composition and distribution of the plaques in excised tissue, the investigators decided to combine Synchrotron spectroscopic techniques with additional imaging methods, Raman spectroscopy and fluorescence microscopy.

>Read more on the Australian synchrotron website

Image Caption: Histology, FTIR, XFM, and tissue autofluorescence imaging of Aβ-plaques