Hidden microglia switch helps protect the brain from Alzheimer’s
A hidden microglial defense system may offer a powerful new way to slow Alzheimer’s.
- Date:
- November 22, 2025
- Source:
- Max Planck Institute for Biology of Ageing
- Summary:
- Scientists discovered that lowering a specific molecule helps microglia switch into a protective state that quiets brain inflammation in Alzheimer’s. A small group of these cells seems to have an outsized ability to keep the brain healthier. When a key signal is removed from them, Alzheimer’s symptoms worsen. This pathway may help explain why some people naturally have reduced Alzheimer’s risk.
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Working with Alzheimer's mouse models, human cells, and donated human brain tissue, researchers found that reducing levels of a molecule called PU.1 can shift microglia into a more protective mode. Microglia are immune cells that live in the brain and help maintain its health. When PU.1 levels drop, these cells increase the production of certain lymphoid immunoregulatory receptor proteins, which are typically involved in managing immune responses in the body.
Although these protective microglia appear in relatively small numbers, the study showed that they have a powerful influence across the brain. Their presence helps calm harmful inflammation, supports cognitive abilities, and improves survival in mice. In contrast, when the team removed CD28 from this rare group of microglia, inflammation rose sharply and plaques associated with Alzheimer's developed more quickly. This outcome demonstrated how essential CD28 is for enabling the helpful actions of these cells.
Microglia as Flexible and Protective Brain Cells
"Microglia are not simply destructive responders in Alzheimer's disease -- they can become the brain's protectors," explained Anne Schaefer, the senior author of the research and leader of the project. She noted that the findings build on earlier work showing that microglia can adopt a wide range of functional states, allowing them to play many different roles in brain health. According to Schaefer, the results also highlight how international scientific partnerships are crucial for making progress in complex fields like neurodegeneration.
Alexander Tarakhovsky added that it was striking to see immune-related molecules, long recognized for their roles in B and T lymphocytes, also influencing microglia. "This discovery comes at a time when regulatory T cells have achieved major recognition as master regulators of immunity, highlighting a shared logic of immune regulation across cell types," he said. He also pointed out that understanding this shared system may open the door to new immunotherapeutic approaches for Alzheimer's disease.
Genetic Clues That Connect PU.1 to Alzheimer's Risk
The work expands on earlier genetic studies by senior co-author Alison Goate, who identified a common variant in SPI1 (the gene responsible for producing PU.1) that is associated with a lower risk of developing Alzheimer's. Goate explained, "These results provide a mechanistic explanation for why lower PU.1 levels are linked to reduced Alzheimer's risk," offering a clearer picture of how genetics influence disease vulnerability.
Overall, the discovery of the PU.1-CD28 axis provides researchers with a new molecular framework for understanding how protective microglial states arise. It also emphasizes the promise of developing treatments that specifically target microglia in order to alter the course of Alzheimer's disease.
Story Source:
Materials provided by Max Planck Institute for Biology of Ageing. Note: Content may be edited for style and length.
Journal Reference:
- Pinar Ayata, Jessica M. Crowley, Matthew F. Challman, Vinaya Sahasrabuddhe, Maud Gratuze, Sebastian Werneburg, Diogo Ribeiro, Emma C. Hays, Violeta Durán-Laforet, Travis E. Faust, Philip Hwang, Francisco Mendes Lopes, Chrysa Nikopoulou, Sarah Buchholz, Robert E. Murphy, Taoyu Mei, Anna A. Pimenova, Carmen Romero-Molina, Francesca Garretti, Tulsi A. Patel, Claudia De Sanctis, Angie V. Ramirez Jimenez, Megan Crow, Felix D. Weiss, Jason D. Ulrich, Edoardo Marcora, John W. Murray, Felix Meissner, Andreas Beyer, Dan Hasson, John F. Crary, Dorothy P. Schafer, David M. Holtzman, Alison M. Goate, Alexander Tarakhovsky, Anne Schaefer. Lymphoid gene expression supports neuroprotective microglia function. Nature, 2025; DOI: 10.1038/s41586-025-09662-z
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