In Alzheimer’s disease, harmful plaques from misfolded amyloid beta proteins form in the brain. However, how these interact with the brain’s immune cells was largely unclear. Using a new imaging technique, researchers have now discovered that a previously unknown subgroup of immune cells accumulates near the plaques. This specialized population produces numerous proteins that indicate an active immune defense. The new findings could possibly provide a basis for better understanding the disease mechanisms and developing new therapies in the long term.
Our brain has its own type of immune cells, microglia. As phagocytes, they remove pathogens and cell debris and regulate inflammatory reactions. However, they are overactive in neurodegenerative diseases such as Alzheimer’s. “It is believed that disease-associated microglial conditions contribute to the progression of Alzheimer’s disease,” explains a team led by Paula Sanchez-Molina from Oregon Health and Science University in Portland. “However, their characterization and research into their connections to pathology remain challenging.” The problem: Detailed analyzes of cell activity usually take place at the single cell level. But the cells in the brain always interact with their environment, so previous studies have only been able to shed light on a small part of the overall picture.
Insights into the interaction of cells
Now Sanchez-Molina and her team have developed a method to gain a more comprehensive insight. To do this, they further developed an imaging technology that has previously been used primarily in cancer research and can be used to visualize numerous different cell types and protein markers at the same time. “With this method called CODEX-CNS, we can in principle capture the entire cellular interaction in the human brain in one image, including pathological changes and interactions between cells,” explains co-author Dennis-Dominik Rosmus from the University of Leipzig.
The researchers examined tissue samples from the frontal cortex of eight people with Alzheimer’s and eight healthy controls who made their bodies available to science after their death. The team made a surprising discovery: “When analyzing brain tissue from body donors, we identified a previously unknown cell population that is closely linked to certain protein deposits in the tissue and that is significantly more common in the Alzheimer’s brain,” reports Rosmus. As the researchers discovered, these cells are a subgroup of microglia that preferentially accumulates near harmful plaques in the brain.
Immunological activity
Further analyzes revealed that these cells, which the researchers call “human plaque-associated microglia,” or HPAM for short, are immunologically very active. Among other things, they apparently present antigens in order to recruit other immune cells. They also produce cellular markers that are associated with phagocytosis, i.e. the breakdown of harmful material. “This could indicate a role for HPAM cells in the clearance of amyloid beta plaques, which could be used therapeutically in the future,” writes the research team. However, further studies are required to determine the exact function and possible therapeutic potential of this special microglia population.
Regardless of the specific application, the CODES-CNS method further developed for the study could also provide new insights into other neurological diseases. “We used CODEX-CNS to examine the brains of Alzheimer’s sufferers, but the method can also be applied to other brain diseases,” explains Rosmus’ colleague Peter Wieghofer. The retina can also be examined more precisely than ever before. “The method opens up new possibilities for personalized medicine and targeted therapies,” says Wieghofer.
Source: Paula Sanchez-Molina (Oregon Health and Science University, Portland, USA), Nature Neuroscience, doi: 10.1038/s41593-026-02267-3