If someone becomes ill with Alzheimer’s disease later in life, even with hindsight, it is generally impossible to pinpoint what caused the dementia in their case. However, we do know that factors such as loss of hearing, lack of exercise or high cholesterol levels can increase the risk. The same is probably also true for infections or traumatic experiences early on in life. Until now it has remained largely unclear how such stressful situations can lead to the deterioration of brain tissue decades later.
“After becoming infected with a pathogen or subjected to extreme stress, the activity of various brain cells changes in the short term,” explains Tomohisa Toda, Professor of Neural Epigenomics at FAU and MPZPM. “For instance, the immune cells in the brain, or microglia, are activated. They trigger an inflammatory reaction, which then settles down again after a certain period. Neurons, the cells responsible for processing information, show a similar reaction pattern: Their activity also changes temporarily before returning to their original state. ”
Cellular “long-term memory” makes brain vulnerable
Normally, the cells return to their normal state. Toda and neuroscientist Prof. Dr. Simon Schäfer from TUM suspect, however, that stressful events may also leave long-term traces in the cells : A type of “ cellular long-term memory ” is formed that permanently changes cells’ activity . Microglia cells may then retain an increased tendency to react to inflammation, while neurons tend to become strongly activated even by mild stressors. Over time, this may lead to the brain’s protective mechanisms becoming weakened and an increased susceptibility for contracting Alzheimer’s disease. “That is at least the hypothesis that we would like to pursue in our project,” says Toda.
The working groups will focus on special, particularly long-lived molecules . A key role is played by what is known as long-lived RNA molecules. While RNAs are normally broken down within hours or even minutes, researchers were able to find long-lived RNA molecules in nerve cells in mice even after a number of years. To put it simply, these molecules can wind themselves around certain areas of DNA. The hypothesis is that in so doing, they have an influence on how the genes that are located in these areas are read, thereby having a long-term effect on cell function.
Long-lived molecules damaged by inflammation and trauma
“We suspect that the long-lived molecules can be damaged by inflammation and trauma, and that this alters their function,” explains TUM researcher Simon Schäfer. “As a result, the stress can continue to make itself felt for a long time: Figuratively speaking, neurons and glia cells remember these stressful experiences, and develop persistently altered response patterns. This then leads to more and more damage accumulating in the brain, until this is finally expressed as the typical symptoms of Alzheimer’s dementia.”
In order to investigate their hypothesis, the research groups will use, among other things, what is known as brain organoids . These are complex tissues that comprise various types of cell and whose composition and compounds are similar to those found in a genuine human brain. Organoids are suitable for modeling the effects of a bacterial or viral infection in an environment similar to a human brain.
“We want to analyze how early stress can have a long-term effect on how glia cells and neurons function,” says Tomohisa Toda. “In the long term, we would like to find out whether this predisposition can be reversed – if so, this may allow us to lower the risk of developing Alzheimer’s. With its program “NEXT – rethink neurodegeneration!”, the Volkswagen Foundation explicitly funds high-risk, exploratory projects with unpredictable returns which could possibly have a fundamental impact on prevention and therapy if they prove successful.