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11/05/2025 17:00
Protective microglia subtype offers potential new therapeutic approach for Alzheimer’s disease
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Scientists have identified a previously unknown protective state of microglia, the brain’s immune cells, that could open up new avenues for treating Alzheimer’s disease.
In Alzheimer’s disease, the most common cause of dementia, microglia – the brain’s immune defense cells – can have both a protective and disease-promoting effect and thus influence the course of the disease. Researchers at the Max Planck Institute for Biology of Aging in Cologne and the Icahn School of Medicine at Mount Sinai in New York, working closely with Rockefeller University, the City University of New York and several international partners, have identified a specific population of neuroprotective microglia. This could reveal a new therapeutic approach for Alzheimer’s disease. In a study published in Nature, the team reports that microglia with reduced expression of the transcription factor PU.1 and simultaneous expression of the lymphoid-like receptor CD28 limit the inflammatory response in the brain (neuroinflammation) and slow the formation of amyloid plaques and the spread of the neurotoxic tau protein. These are the main hallmarks of Alzheimer’s disease.
Using Alzheimer’s mouse models, human cells and human brain tissue, the researchers were able to demonstrate that a reduction in PU.1 promotes the expression of receptor proteins of the lymphoid immune system on microglia. Although present in small numbers, these neuroprotective microglia exert a protective effect on the brain, helping to maintain cognitive function and survival in mice. Removing CD28 from this small subset of microglia increased inflammation and accelerated plaque growth. This highlights the key role of CD28 in the protective effects of microglia.
“Microglia are not just destructive antagonists in Alzheimer’s disease – they can become protectors of the brain,” said Anne Schaefer, senior author of the study and leader of the project. “This finding extends our previous observations on the remarkable plasticity of microglial states and their important role in various brain functions. It also underscores the critical importance of international collaboration for scientific progress.”
“It is noteworthy that molecules that immunologists have long associated with B and T lymphocytes also regulate microglial activity,” added Alexander Tarakhovsky. “This discovery comes at a time when regulatory T cells are receiving significant attention as master regulators of immunity and a common logic of immune regulation across different cell types is becoming apparent. It also paves the way for immunotherapeutic strategies to treat Alzheimer’s disease.”
The study builds on the groundbreaking genetic work of Alison Goate. She is one of the study’s lead co-authors. She has identified a common variant of the SPI1 gene, which encodes the PU.1 protein. This variant is associated with a reduced risk of Alzheimer’s disease. “These results provide a mechanistic explanation for why lower PU.1 levels are associated with a reduced risk of Alzheimer’s disease,” Goate said.
The discovery of the PU.1–CD28 axis provides a molecular framework for understanding protective microglial states and highlights the potential of microglia-targeted immunotherapies to alter the course of Alzheimer’s disease.
Contact for scientific information:
Anne Schaefer, Director Max Planck Institute for Biology of Aging, aschaefer@age.mpg.de
Original publication:
Ayata, Crowley, Challman et al., Lymphoid gene expression supports neuroprotective microglia function. Nature, DOI: 10.1038/s41586-025-09662-z.
More information:
Images
Microglia (green) respond to aggregated beta-amyloid plaques (blue) in the cortex of a mouse.
Source: Jessica M. Crowley
Copyright: Jessica M. Crowley
Criteria of this press release:
Journalists
Biology, Medicine
transregional, national
Research results
German
