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Protective Microglia Subtype Offers Potential New Therapeutic Pathway in Alzheimer\u2019s Disease
International research team identifies distinct population of neuroprotective immune cells of the central nervous system<\/p>\n
New York, NY (November 5, 2025) \u2013 In Alzheimer\u2019s disease, the leading cause of dementia, microglia\u2014the brain\u2019s immune defenders\u2014can act as both protectors and aggressors, shaping how the disease progresses.<\/p>\n
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\u2019s disease.<\/p>\n
In a study published November 5 in Nature<\/a> [DOI:], 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\u2019s pathology.<\/p>\n 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.<\/p>\n Using Alzheimer\u2019s 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\u2019s key role in protective microglial activity.<\/p>\n \u201cMicroglia are not simply destructive responders in Alzheimer\u2019s disease\u2014they can become the brain\u2019s protectors,\u201d 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. \u201cThis 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\u00a0in advancing scientific progress.\u201d<\/p>\n \u201cIt is remarkable to see that molecules long known to immunologists for their roles in B and T lymphocytes also regulate microglial activity,\u201d added\u00a0Alexander Tarakhovsky, MD, PhD, Dr. Plutarch Papamarkou Professor of Immunology, Virology, and Microbiology at The Rockefeller University and co-author of the paper. \u201cThis 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\u2019s disease.\u201d<\/p>\n The study builds on pioneering genetic work by\u00a0Alison M. Goate, DPhil, Jean C. and James\u00a0W. Crystal Professor of Genomics and Chair of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine, founding director of the\u00a0Ronald M. Loeb Center for Alzheimer\u2019s Disease at Mount Sinai<\/a>, and a senior co-author of the study, who identified a common variant in\u00a0SPI1\u2014the gene encoding PU.1\u2014as being associated with reduced Alzheimer\u2019s risk.<\/p>\n \u201cThese results provide a mechanistic explanation for why lower PU.1 levels are linked to reduced Alzheimer\u2019s disease risk,\u201d said Dr. Goate.<\/p>\n The discovery of the PU.1-CD28 axis\u00a0establishes a molecular framework for understanding protective microglial states and highlights the potential of microglia-targeted immunotherapies\u00a0to modify the course of Alzheimer\u2019s disease.<\/p>\n This work was funded by the National Institutes of Health, European Research Council, Stavros Niarchos Foundation, Cure Alzheimer\u2019s Fund, Freedom Together Foundation, Belfer Neurodegeneration Consortium Grant, Massachusetts Life Sciences Center, Robin Chemers Neustein Postdoctoral Fellowship Award, Alfred P. Sloan Foundation, Alzheimer\u2019s Association, BrightFocus Foundation, National Multiple Sclerosis Society, Clinical and Translational Science Awards.\u00a0<\/p>\n About the Mount Sinai Health System 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\u2019 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\u202fNewsweek\u2019s\u00ae\u202f\u201cThe World\u2019s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals\u201d and by\u202fU.S. News & World Report’s\u00ae\u202f\u201cBest Hospitals\u201d and \u201cBest Children\u2019s Hospitals.\u201d The Mount Sinai Hospital is on the\u202fU.S. News & World Report\u00ae\u202f\u201cBest Hospitals\u201d Honor Roll for 2025-2026.\u00a0\u00a0<\/p>\n For more information, visit\u202f<\/a>https:\/\/www.mountsinai.org<\/a>\u202for find Mount Sinai on\u202f<\/a>Facebook<\/a>,\u202fInstagram<\/a>,\u202fLinkedIn<\/a>,\u202fX<\/a>, and\u202f<\/a>YouTube<\/a>.<\/p>\n ###<\/p>\n \t\t\t\t\t\t\t\t\t\t
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