Following the tracks of Alzheimer’s disease

Martin Hallbeck has a foot in two camps: he works not only in research but also as a doctor and head of clinical pathology. His research aims to find out how neurodegenerative diseases spread in the brain and how they can be stopped.

the researchers in the cell culture roomThe cell culture lab is the site of many experiments that increase our knowledge of neurodegenerative diseases. Photo credit: Kajsa Juslin In neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, the breakdown of nerve cells always starts in a specific region of the brain. The disease then spreads to regions that are anatomically connected to the initial site, similar to the way in which a fire can spread through the ventilation system of a building.

“The spread of the disease follows a pattern. This is evidence that the spread follows the connections in the brain. We see this in many neurodegenerative diseases, although they start in different parts of the brain and spread at different speeds”, says Martin Hallbeck, associate professor at Linköping University and senior consultant of clinical pathology at Linköping University Hospital.

His research group was the focus of intense international attention in 2012, when they were the first to show how the disease spreads between nerve cells. In Alzheimer’s disease, misfolded forms of two proteins known as amyloid-ß and tau form aggregates. As time passes, they form ever-increasing deposits in the brain. Martin Hallbeck and his group labelled small fragments of the amyloid-ß deposits with a “flag” that shone red in the microscope, and then applied these fragments to nerve cells. They then allowed the cells to grow together with nerve cells labelled with a green flag, which enabled the researchers to distinguish between them.Martin HallbeckMartin Hallbeck. Photo credit: Emma Busk Winquist

“We saw that the cells formed contacts, and the red amyloid aggregate passed into the green cells. We were also able to show that the protein aggregates damaged the recipient cell,” says Martin Hallbeck.

Following this breakthrough six years ago, the Linköping researchers and other researchers around the world have confirmed that the spread takes place, and that it proceeds by several mechanisms. The researchers in Martin Hallbeck’s group are finding out what happens at the connections between cells when the disease spreads. One thing that they have started to consider is the similarity between neurodegenerative diseases and some other diseases.

“One important way of achieving progress in science is to pass ideas and knowledge between research fields. At the cellular level, diseases often show similarities. Even if not everything happens in the same way, there may be lessons to learn and research tools in the field of, for example, research into viruses that can be used also in Alzheimer’s research”, says Martin Hallbeck.

One very recent study that is soon to be published describes parallels they have discovered between virus infections and the spread of neurodegenerative diseases.

“We have looked at studies that identify the cellular proteins involved when viruses, such as the HIV virus, spread. We have been able to show that proteins associated with neurodegenerative diseases mimic the way in which viruses spread from one cell to another, by taking over the same cellular systems”, says Juan F. Reyes, postdoc in the research group.

The toxic aggregates of protein can also move between cells through membrane-covered droplets known as exosomes. Researchers have previously considered the exosomes to be a kind of rubbish bag, that in principle all the cells in the body use to get rid of waste. It has, however, turned out that exosomes play an important role in the communication between cells, including cells in the brain. Furthermore, the researchers have shown that the misfolded proteins can “hitch a lift” with the exosomes. In experiments on cultured cells, the Linköping researchers have managed to reduce the spread of proteins by exosomes. They are hoping that these research results will in the long run form the basis for new drugs. There is, of course, a long way to go, and many questions must be answered.the researchers are having a discussion in front of a whiteboardJuan F. Ryes and Martin Hallbeck discuss a critical issue in Alzheimer research. How can toxic aggregates of protein spread from one cell to another? Photo credit: Kajsa Juslin

“We must confirm that the mechanisms we are trying to inhibit are sufficiently significant in the spread of the disease. And we must also confirm that the processes are active during a stage of the disease in which we can treat the patients. It cannot be at such an early stage of the disease that the diagnosis has not been made, nor can it be too late in the disease progression. And we must find out whether it is possible to block these mechanisms without giving severe undesired effects”, says Martin Hallbeck.

Most researchers today believe that the treatment strategies of the future must attack several disease mechanisms at the same time, in the same way that cancer is often treated with a combination of drugs. When it comes to the question of finding new cures, Martin Hallbeck is full of hope.

“We must realise that these diseases are much more complicated than we thought. There are no easy solutions. But understanding the differences and similarities between diseases in different patients will allow us to find mechanisms that can be the target of new treatments. We’re going to need time, work and money to reach our goals, but I’m convinced that it’s possible.”

The article (in Swedish) has been published in the magazine Forskning & Utveckling no. 1/2018, published by the Faculty of Medicine and Health Sciences at LiU and Region Östergötland.

Translation: George Farrants


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