Protective microglia subtype offers potential new therapeutic pathway in Alzheimer’s disease

In Alzheimer’s disease, the leading cause of dementia, microglia—the brain’s immune defenders—can act as both protectors and aggressors, shaping how the disease progresses.

Researchers from the Icahn School of Medicine at Mount Sinai, in close collaboration with colleagues at the Max Planck Institute for Biology and Ageing in Cologne, Germany, and at The Rockefeller University, The City University of New York, and other international partners, have identified a distinct population of neuroprotective microglia that may point to a new therapeutic approach for Alzheimer’s disease.

In a study published November 5 in Nature [DOI: 10.1038/s41586-025-09662-z], the team reports that microglia that have reduced expression of the transcription factor called PU.1, and that also have co-expression of the lymphoid-like receptor CD28, act to limit neuroinflammation and to slow amyloid plaque build-up and neurotoxic tau protein spreading in the brain, the major hallmarks of Alzheimer’s pathology.

PU.1 is a protein that binds to specific DNA sequences to control the translation of genetic information, determining when and how genes are turned on or off. CD28 is a co-stimulatory receptor found on the surface of T cells that helps initiate and sustain an effective adaptive immune response.

Using Alzheimer’s mouse models, human cells, and human brain tissue, the researchers demonstrated that lowering PU.1 promotes the expression of lymphoid immunoregulatory receptor proteins on microglia. Despite being present in small numbers, these neuroprotective microglia exert a brain-wide suppressive impact on inflammation and protect cognitive function and survival in mice. The researchers found that deleting CD28 from this small subset of microglia amplified inflammation and accelerated plaque growth, highlighting CD28’s key role in protective microglial activity.

“Microglia are not simply destructive responders in Alzheimer’s disease—they can become the brain’s protectors,” said Anne Schaefer, MD, PhD, Professor in the Nash Family Department of Neuroscience at the Icahn School of Medicine, Co-Director of the Center for Glial Biology at The Friedman Brain Institute, Director of the Max Planck Institute for Biology of Ageing, and senior author of the paper. “This finding extends our earlier observations on the remarkable plasticity of microglia states and their important roles in diverse brain functions. It also underscores the vital importance of international collaboration in advancing scientific progress.”

“It is remarkable to see that molecules long known to immunologists for their roles in B and T lymphocytes also regulate microglial activity,” added Alexander Tarakhovsky, MD, PhD, Dr. Plutarch Papamarkou Professor of Immunology, Virology, and Microbiology at The Rockefeller University and co-author of the paper. “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. It also paves the way for immunotherapeutic strategies for Alzheimer’s disease.”

The study builds on pioneering genetic work by Alison M. Goate, DPhil, Jean C. and James W. Crystal Professor of Genomics and Chair of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine, founding director of the Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, and a senior co-author of the study, who identified a common variant in SPI1—the gene encoding PU.1—as being associated with reduced Alzheimer’s risk.

“These results provide a mechanistic explanation for why lower PU.1 levels are linked to reduced Alzheimer’s disease risk,” said Dr. Goate.

The discovery of the PU.1-CD28 axis establishes a molecular framework for understanding protective microglial states and highlights the potential of microglia-targeted immunotherapies to modify the course of Alzheimer’s disease.

This work was funded by the National Institutes of Health, European Research Council, Stavros Niarchos Foundation, Cure Alzheimer’s Fund, Freedom Together Foundation, Belfer Neurodegeneration Consortium Grant, Massachusetts Life Sciences Center, Robin Chemers Neustein Postdoctoral Fellowship Award, Alfred P. Sloan Foundation, Alzheimer’s Association, BrightFocus Foundation, National Multiple Sclerosis Society, Clinical and Translational Science Awards. 

About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it. 

Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report® “Best Hospitals” Honor Roll for 2025-2026. 

For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Instagram, LinkedIn, X, and YouTube.

###