Alzheimer's not only affects memory, but also the brain's immune system - but not in the same way everywhere. Researchers from the Faculty of Medicine at the University of Freiburg have now discovered in an animal model that in Alzheimer's disease, only those microglial cells that are further away from the typical protein deposits in the brain - known as plaques - react to external stimuli. If these immune cells can be specifically activated, Alzheimer's-typical changes in the brain are significantly delayed. The study was published on July 14, 2025 in the journal Nature Neuroscience.

“For the first time, we were able to see how quickly the immune system in the brain reacts to Alzheimer's - and that only microglial cells that are further away from the protein deposits respond at all to external stimuli such as infections or bacterial colonization,” says Prof. Dr. Marco Prinz, Medical Director of the Institute of Neuropathology at the Freiburg University Medical Center and member of the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling at the University of Freiburg. “By specifically activating these immune cells, we were able to slow down Alzheimer's in a mouse model.”

Cell response changes during the course of the disease

Microglial cells perform important tasks in the healthy brain. In Alzheimer's disease, they change - especially in the vicinity of so-called amyloid plaques. Using a newly developed staining technique, the researchers were able to distinguish between different cell groups for the first time and observe how differently they react to stimuli. Only those microglial cells that were not located directly on the deposits were altered by external influences. “Our study shows for the first time how important the spatial location of immune cells in the brain is for their function in Alzheimer's disease,” explains Jun. Prof. Dr. Katrin Kierdorf, research group leader at the Institute for Infection Prevention and Hospital Hygiene at the Freiburg University Medical Center and also a CIBSS member. The team also succeeded in deciphering the molecular causes of this gradual loss of function of individual cell groups in detail.

The next step is to investigate the extent to which the results can be transferred to humans and what this means for the development of new therapeutic approaches. “The targeted activation of a specific signaling pathway in these cells could be a promising approach to slow down the disease process,” says Kierdorf. The study was conducted together with colleagues from the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE) Freiburg and the University Hospital of Bern, Switzerland.

Original publication:

Alberto Ardura-Fabregat, Lance Fredrick Pahutan Bosch, Emile Wogram, Omar Mossad, Roman Sankowski, Philipp Aktories, Lina Kieger, James Cook, Dilara Hasavci, Hatice Ulupinar, Daniel Brock, Fang Wang, Nicola Iovino, Samuel Wald, Sebastian Preissl, Bahtiyar Yilmaz, Daniel Schnepf, Andrew J. Macpherson, Thomas Blank, Katrin Kierdorf & Marco Prinz (2025): Response of spatially defined microglia states with distinct chromatic accessibility in a mouse model of Alzheimers disease. Nature Neuroscience: DOI: 10.1038/s41591-023-02673-1

CIBSS profile of Prof. Dr. Marco Prinz

CIBSS profile of Jun. Prof. Dr. Katrin Kierdorf

Original press release University of Freiburg