Researchers Discover Immune Cells That May Combat Alzheimer’s

Researchers at the Icahn School of Medicine at Mount Sinai have made significant strides in understanding Alzheimer’s disease by identifying immune cells in the brain that could help slow its progression. These findings, published on November 5, 2025, in the journal Nature, reveal how specific microglia—immune cells in the brain—can reduce inflammation and block the spread of harmful proteins associated with the disease.

Alzheimer’s disease is the most common cause of dementia, and the role of microglia is complex. While these cells can protect the brain by clearing debris, they can also contribute to damage and inflammation under certain conditions. The research team, collaborating with scientists from the Max Planck Institute for Biology and Ageing in Cologne, Germany, and other institutions, discovered a unique subset of microglia that appear to offer protective benefits against Alzheimer’s.

In the study, researchers found that microglia exhibiting low levels of a transcription factor known as PU.1 and high expression of a receptor called CD28 play a crucial role in controlling inflammation in the brain. These specialized microglia not only help slow the buildup of amyloid plaques but also inhibit the spread of toxic tau proteins, both of which are hallmark features of Alzheimer’s.

How these protective microglia function is particularly noteworthy. Using mouse models of Alzheimer’s, as well as human brain cells and tissue samples, the team demonstrated that lowering PU.1 levels prompts microglia to express receptors typically found in lymphoid cells, which are vital for immune regulation. Although this protective subset constitutes only a small portion of total microglia, their influence is significant, as they help suppress widespread inflammation and preserve memory in mice.

When the researchers removed CD28 from this microglial subset, they observed an increase in inflammation and plaque formation. This confirmed that CD28 is essential for maintaining the protective capabilities of these cells.

Anne Schaefer, MD, PhD, a professor in the Nash Family Department of Neuroscience at the Icahn School of Medicine and a senior author of the study, stated, “Microglia are not simply destructive responders in Alzheimer’s disease—they can become the brain’s protectors.” She emphasized the importance of international collaboration in advancing scientific understanding of complex conditions like Alzheimer’s.

In addition, Alexander Tarakhovsky, MD, PhD, from The Rockefeller University, noted that this discovery highlights how molecules known for their roles in B and T lymphocytes also influence microglial activity. He pointed out that the findings pave the way for new immunotherapeutic strategies targeting Alzheimer’s disease.

The study also builds on prior genetic research led by Alison M. Goate, DPhil, who identified a genetic variant in the SPI1 gene, responsible for producing PU.1, linked to a reduced risk of developing Alzheimer’s disease. Dr. Goate commented, “These results provide a mechanistic explanation for why lower PU.1 levels are linked to reduced Alzheimer’s disease risk.”

The relationship between PU.1 and CD28 opens up a new molecular framework for understanding microglial functions and suggests that targeting these immune cells could significantly alter the course of Alzheimer’s.

This research was supported by several prestigious organizations, including the National Institutes of Health, the European Research Council, and the Alzheimer’s Association, among others. The findings represent a pivotal step forward in the quest for effective therapies for Alzheimer’s disease, offering hope to millions affected by this devastating condition.