The brain has its own immune system. So-called microglial cells comb through the thinking organ in search of intruders or injuries. When they encounter substances that are harmful to the brain, they become active and cause inflammatory processes. This mechanism is actually a good thing for warding off germs and toxins. But when microglial cells encounter deposits of the body’s own amyloid-beta protein, the inflammation leads to irreversible damage to the brain tissue. “When that happens, a vicious circle of damaging reactions is triggered. Nerve cells break down and the brain can actually become pitted,” explains Prof. Dr. Bernd Bufe the process.
The exact reasons why amyloid beta triggers this damage is only partially understood. There are more than a hundred variants of amyloid beta, of which only two or three have been well studied to date. “Our results indicate that it is very important to take a closer look at the little-studied variants in particular,” notes the research group leader. The research group has identified three receptors that can recognize a particularly large number of these variants. Some of them are even more common in the brain than the previously well-studied forms.
The precise role of the receptors in the brain is currently unclear. The research group hypothesized that one of the newly found receptors (FPR1) triggers an inflammatory response following exposure to amyloid beta, while another receptor (FPR2) is believed to help limit damage to nerve cells in the brain. According to the measurement data of the working group, this unfortunately only reacts with larger amounts of amyloid beta, which means that a lot of damage may have already occurred in the body beforehand. Therefore, it might make sense to use drugs to activate the helpful receptor and block the damaging receptor in order to limit the immune response in the brain. Almost nothing is currently known regarding the third receptor (FPR3). Since it does not occur in the brain, its involvement in Alzheimer’s is only possible in late stages of the disease.
For the further investigation of these receptors in cell models, the working group on the Zweibrücken campus of the Kaiserslautern University of Applied Sciences finds almost ideal conditions for such work. “Our laboratory equipment in the working group can compete with that of Leibnitz institutes,” says Prof. Dr. Bufe convinced. Doctoral student Lukas Busch also studied here and reports: “The Applied Life Sciences course at Kaiserslautern University of Applied Sciences is extremely modern and prepares you for many professional fields. My fellow students now work for well-known companies such as Biontech or Boehringer.”
Not least for this reason, the Zweibrücker researchers have so far mainly examined the reaction of the receptors in cell culture experiments. In the next phase of their research project, they will primarily try to confirm their findings in mouse models. If all goes well, the end result might be a drug that halts or slows the onset of Alzheimer’s. “Studies by colleagues are already showing encouraging results in animal models. That’s why we’re currently applying for funds for further research,” explains Prof. Dr. Bufe, “unfortunately it is becoming increasingly difficult in Germany to get animal experiments approved.” Of course, he thinks it makes sense to protect the animals as much as possible, but new, extremely strict application procedures and long inflexible approval procedures made it possible for the scientists in the Federal Republic increasingly impossible to continue their research in animal models. “I know a few colleagues who will have to give up animal experiments this year because they can no longer cope with the bureaucratic effort and the high costs, although these experiments will continue to be indispensable for drug development in the coming decades,” says Prof. Bufe. It is therefore gratifying that the working group has already succeeded in leading the renowned research group of Prof. Dr. Frank Kirchhof from the University Hospital Homburg/Saar for a collaboration. Together they plan to directly observe inflammatory processes typical of Alzheimer’s in the living mouse brain and to alleviate the inflammatory reactions by administering receptor agents.
Further information:
Forschungsarbeit: Amyloid beta and its naturally occurring N-terminal variants are potent activators of human and mouse formyl peptide receptor 1“ Busch L, Al Taleb Z, Tsai YL, Nguyen VTT, Lu Q, Synatschke CV, Endres K, Bufe B: Journal of Biological Chemistry. DOI:10.1016/j.jbc.2022.102642
Review article: The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease. Busch L, Eggert S, Endres K, Bufe B. Cells. DOI: 10.3390/cells11213421.
