More than a hundred years after the psychiatrist Alois Alzheimer described the characteristics of the disease that bears his name, the significant gaps that exist in our understanding of how and why the disease develops mean that we still do not have effective treatments .
Alzheimer’s identified protein deposits that had accumulated in the brain of a patient who died of dementia. Since then, research has largely focused on the protein fragments, known as beta amyloid, that make up these toxic plaques . The theory goes as follows: If we can clean these plaques, then we can prevent brain cells from dying.
Despite billions of euros invested in research, there is little to show patients. Current treatments can only mask symptoms for a while, but there is still no way to stop or even slow the progress of the underlying disease.
One of the main difficulties in finding an effective treatment is that it is difficult to recreate Alzheimer’s disease in the laboratory. It is not developed by any other animal, and studies often rely on genetically modified mice as models of the disease.
“We have hundreds of drugs that work well and improve the outcome of mice when they have symptoms similar to Alzheimer’s disease. So there is a complete translational lockdown from preclinical (animal) to clinical (human) studies, “said Professor Jari Koistinaho from the University of Eastern Finland.
The fundamental challenge is that we do not yet know how Alzheimer’s disease is triggered . The early stages could begin decades before symptoms appear, making it extremely difficult to understand how those early moments influence everything that follows. Finding out this could help create models that more closely represent the disease we see in people.
Wrong display
Amyloid beta is a chain of amino acids and, like the cables in headphones or chargers, it can easily become entangled. This disorder has long been known to be responsible for beta amyloid clumping together to form the hallmark plaques of Alzheimer’s.
While at first glance the plaques in different people may appear the same, recent research suggests that there could be variation in the way unfolding occurs at the molecular level.
Professor Mathias Jucker, from the German Center for Neurodegenerative Diseases, studied the impact of these different splittings as part of the REframe project. “The question was very simple: does it matter?” He said. “In some people the disease can develop in a couple of years; in others it can be 12 to 15 years. Is the conformation of the misfolded protein that drives the disease?”
By studying mice that had beta amyloid misfolded in different ways, Prof. Jucker showed that these changes influence the way the disease progresses. To see if this also occurs in humans, he and his colleagues studied the brains of 40 people who died with Alzheimer’s disease. They were able to see differences in amyloid beta cleavage between groups of people in which inherited genetic mutations caused the disease and in cases where it was not in families.
These early results provide a link between the initial cause of the disease and the way the protein is unfolded. However, when you study the brains of people who have died from the disease, it is in its last stage, many years after the first trigger, says Prof. Jucker. “It is very difficult to prove in humans in the final stage what happened before.”
Risks
An added complexity is that most cases of Alzheimer’s disease are not caused by a single genetic mutation, but by a complex mix of factors that influence overall risk, both genetic and environmental.
Dr. Stéphane Oliet from the University of Bordeaux, France, is part of the DACAPO-AD project, which aims to understand the effect that different risk factors for Alzheimer’s disease have on the brain. To do this, Dr. Oliet is monitoring the communication between neurons across synapses and how it changes over time.
The most prominent genetic risk factor is a gene called ApoE, where a particular variant can increase the risk of Alzheimer’s disease up to 15 times. In mice with this genetic variant, Dr. Oliet could see communication problems between synapses in the hippocampus, the brain’s center for memory formation.
“The synaptic deficits that we are seeing are what we observe before any neurodegeneration or cell death occurs ,” said Dr. Oliet. “If the two are linked, if the synaptic deficit is prevented before cell death occurs, maybe we can prevent or at least delay cell death.”
The reasons for the changes in neurons are not yet clear, but Dr. Oliet suspects that neighboring cells called astrocytes could be responsible . These cells help support neurons by providing nutrients and repairing damage.
In previous work on mice with a different gene mutation, Dr. Oliet found that astrocytes had trouble producing a particular amino acid necessary for synaptic activity.
Dr. Oliet showed that giving mice a dose of the missing amino acid helped reduce synaptic deficits. If you can confirm that this works in mice with different risk factors for Alzheimer’s, then hope is raised that it might work in humans as well. “It would be great, it would be probably the most exciting result of this study, if we could find a common mechanism between the different models of Alzheimer’s disease,” he said.
It is clear that astrocytes were completely ignored for many years. They have been regarded as the babysitters and garbage cans of our brain. Now we know that they do more than that, they have an active role in the synapse.
Turn back the clock
If astrocytes are an important part of the development of Alzheimer’s disease in mice, the question remains whether this is a good model for what is happening in people.
“If we compare the genetic difference between man and mouse, there is not that much difference in neurons, but the biggest difference in gene expression is in astrocytes,” said Prof. Koistinaho.
As a specialist in stem cell research, he is leading the MADGIC project to develop better models of Alzheimer’s disease. To do this, he is using a technique to transform a person’s skin cells into induced pluripotent stem cells, a type of base cell that can develop into a variety of brain cells, such as neurons and astrocytes. These transformed cells carry the same genes and mutations as the original person. This gives scientists a way to see how these brain cells develop in someone at high risk for Alzheimer’s disease.
“They do not represent the brain cells of a 60-year-old patient, but the way the cells were in the brain before and after birth. So we are turning the clock back a bit, “said Prof. Koistinaho.
To see how these cells change as they age, he transplanted the cells into newborn mice. During his first year of life, there was no noticeable difference. However, when the mice were past “middle age” in their second year, there were signs of differences in their memory.
The findings so far suggest that astrocytes carrying an Alzheimer’s-causing mutation alter the behavior of surrounding brain cells in mice. With further analysis, the team hopes to have a clearer idea of how these changes could lead to the accumulation of beta amyloid and fill in some of the missing links between the causes of Alzheimer’s and the effect.
Artículo original
This article was originally published in Horizon, the EU Research and Innovation Magazine
