IL-12 targeting could open pathways for new Alzheimer’s treatments

Researchers from Charité-Universitätsmedizin Berlin and the Max Delbrück center have detailed the precise mechanism with which the inflammatory signal molecule IL-12 contributes to Alzheimer’s disease. The study was published in the magazine “Nature Aging”.

Microglia, the immune cells of the brain, usually serve as diligent guardians. They eliminate intruders such as microbes and clean up cellular debris – including the plaques that are typical of Alzheimer’s disease. However, as our brains get older, Microglia also change. Although some continue to function effectively, others gradually lose their protective role and they start to separate small amounts of inflammatory messengers.

Such a messenger is Interleukine-12 (IL-12). Due to meticulous analyzes, research teams led by Professor Frank Heppner, director of the Neuropathology department of Charité-Universitätsmedizin Berlin, and Professor Nikolaus Rajewsky, director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center. Their study, published in “Nature Aging”, could pave the way for new combination therapies.

For decades, Alzheimer’s research concentrated almost exclusively on amyloid-beta and tau deposits, while inflammation was considered a side effect. Only recently did we start acknowledging that inflammatory processes can be a primary engine for disease progression. “

Professor Frank Heppner, director of the Neuropathology department at Charité – Universitätsmedizin Berlin

In 2012, the Heppner lab reported in natural medicine that blocking IL-12 and IL-23 significantly reduced the brain changes of Alzheimer’s in mice. “But we could not unravel the underlying mechanism with standard techniques,” explains Heppner. He reasoned that some cell analysis could give more decisive instructions, so he asked Rajewsky to work together.

Sticky and confused brain cells

During life, cells refer to their genetic instructions to respond to external stimuli. Researchers use single -cell analyzes to observe this process and reconstruct which genes are read and translated into proteins into thousands of individual cells at the same time. These analyzes generate huge data sets, which can now be analyzed with the help of artificial intelligence and machine learning. However, a major challenge in the use of a few cell sequence technology is to insulate individual cells from a tissue sample without damaging them or causing unintended changes. “In aging mouse brain – especially those with the plaques of Alzheimer’s – cells are so stuck and confused that they neatly separate is almost impossible,” explains Rajewsky.

His team spent a number of years perfecting a solution. Instead of insulating whole cells, they extract cell nuclei from brain tissue and analyze the RNA in every cell. Through cross -reference with publicly available data, such as the Allen Brain Atlas, they can ensure that their method offers a representative snapshot of all cell populations. For the current study, they have given RNA Seasquenced of more than 80,000 cell nuclei and developed specialized workflows to process the data. They also reconstructed communication between cells. “Our teams repeatedly sat together to try to interpret this very complex data,” says Rajewsky. “This meticulous early optimization was crucial – without we could not have detected these connections.”

How IL-12 damages Alzheimer’s brains

IL-12, previously best known for its role in autoimmune diseases such as Crohn’s disease and rheumatoid arthritis, seems to play a crucial role in Alzheimer’s progression. It damages two important brain cell types: adult oligodendro -drocytes, which normally produce myelin – the cool insulating layer around nerve fibers that are essential for rapid signal transmission; And internurons, which are especially important for cognition and memory. IL-12 binding to interneurons ensures that they die. A vicious circle starts: as more microglia IL-12 produce, more brain cells support damage. In the meantime, the remaining functional microglia is overloaded by the task to erase the extra cellular debris, and therefore do not remove the Alzheimer’s plaques.

To verify this mechanism, researchers have tested it in mice and in human tissue. When the Heppner IL-12 team blocked in cell cultures and mouse models, they were able to strain on disease-related changes. Electron microxes of mouse brain tissue taken at the Max Planck Institute for Multidisciplinary Sciences in Göttingen also showed how myelin structure and nerve fiber density changed, depending on whether the IL-12 signaling route was present or was absent. Mass spectrometric analyzes (lipidomics) at the University of Zurich confirmed the changed composition of the high -fat insulation layer. Study of autopsy tissue of the patients of Alzheimer’s caused further confirmation of the results-how more advanced the disease, the more IL-12 was present in the tissue. Cell cultures with human oligodendrocytes were also extremely sensitive to IL-12.

Potential combination therapy

“We now have a very detailed image of this mechanism, with single-cell technologies that serve as a crucial catalyst. The only remaining question is which cell type IL-12 has first consequences, internurons, or both simultaneously,” says Heppner Zentum Zentumtumtumtum (Dzne).

The study has immediate implications because there are already medicines on the market that block IL-12. The researchers hope that clinicians will build on their findings and initiate clinical tests. “If these drugs turn out to be effective, they would be a new arrow in the arrow cooker. Alzheimer’s not only has one cause. One axis of the disease is also controlled by the immune system, at least in some patients. The delay of neurodegeneration requires combination therapy,” Heppner emphasizes. Such an approach could start early in the disease process, because IL-12 can be measured in blood or cerebrospinal fluid, he adds.

In the meantime, the Charité and the Max Delbrück Center teams are investigating a new hypothesis: can microplastic drive microglia in the brain to produce IL-12? “Microglia may have difficulty processing microplastic, causing inflammatory reactions,” suggests Rajewsky. “This can reveal a connection between environmental factors and widespread diseases.” Although unproven, both teams consider it a compelling and important research direction.