Scientists find brain cells that can stop Alzheimer’s disease

Scientists from the Icahn School of Medicine at Mount Sinai, in collaboration with researchers from the Max Planck Institute for Biology and Aging in Cologne, Germany, Rockefeller University, the City University of New York, and other international partners, have identified a unique population of microglia that appears to protect the brain. This discovery could pave the way for new treatment strategies aimed at slowing or preventing Alzheimer’s disease.

In a study published on November 5 natureThe team found that microglia with lower levels of a transcription factor called PU.1 and higher expression of a receptor known as CD28 help reduce brain inflammation. These specialized microglia also slow the buildup of amyloid plaques and the spread of toxic tau proteins, both of which are key hallmarks of Alzheimer’s disease.

PU.1 is a protein that binds to specific regions of DNA, helping to control which genes are activated or silenced. CD28, located on the surface of T cells, acts as a signaling receptor that supports immune cell activation and communication.

How do protective microglia work?

Using mouse models of Alzheimer’s disease, as well as human brain cells and tissue samples, the researchers showed that reducing PU.1 levels encourages microglia to express immune-regulating receptors normally found on lymphocytes. Although these protective microglia make up only a small fraction of the total microglia population, their effect is widespread: they suppress inflammation throughout the brain and help maintain memory and survival in mice.

When the scientists removed CD28 from this specific subset of microglia, inflammation worsened and plaque growth increased, confirming that CD28 plays an essential role in keeping these brain-protective cells active.

“Microglia are not just destructive effectors in Alzheimer’s disease — they can become protectors of the brain,” said Anne Schiffer, MD, PhD, Nash Family Professor of Neuroscience at the Icahn School of Medicine, co-director of the Center for Microglial Biology at the Friedman Brain Institute, director of the Max Planck Institute for the Biology of Aging, and senior author of the paper. “This discovery expands our previous 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 striking to see that molecules long known to immunologists for their roles in B and T lymphocytes also regulate microglia activity,” added Alexander Tarakhovsky, MD, PhD, the Plutarch Papamarkou Professor of Immunology, Virology and Microbiology at The Rockefeller University and a co-author of the paper. “This discovery comes at a time when regulatory T cells have achieved significant recognition as master regulators of immunity, highlighting the common logic of immune regulation across cell types. It also paves the way for immunotherapy strategies for Alzheimer’s disease.”

Genetic evidence suggests a lower risk of developing Alzheimer’s

The research expands on previous genetic findings by Allison M. Gott, Ph.D., Ph.D., and Jan 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 Alzheimer’s Disease Center at Mount Sinai, and co-senior author of the study. Dr. Gott’s previous work identified a common genetic variant in SPI1 (the gene responsible for producing PU.1) that is associated with a reduced risk of developing Alzheimer’s disease.

“These findings provide a mechanistic explanation for why lower PU.1 levels are associated with a lower risk of developing Alzheimer’s disease,” Dr. Goat said.

A new path toward immunotherapy for Alzheimer’s disease

The discovery of the relationship between PU.1 and CD28 provides a new molecular framework for understanding how microglia protect the brain. It also reinforces the idea that targeting microglia activity through immune-based therapies could alter the course of Alzheimer’s disease.

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