Scientists find brain cells that could stop Alzheimer’s

Scientists from the Icahn School of Medicine at Mount Sinai, together with researchers from the Max Planck Institute for Biology and Ageing in Cologne, Germany, The Rockefeller University, The City University of New York, and other international partners, have identified a unique group of microglia that appear 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 November 5 in Nature, the 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, which are both major hallmarks of Alzheimer's.

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

How Protective Microglia Work

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

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

"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."

Genetic Clues Point to Lower Alzheimer's Risk

The research expands upon earlier genetic findings 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. Dr. Goate's prior work identified a common genetic variant in SPI1 (the gene responsible for producing PU.1) that is linked to a lower risk of developing Alzheimer's disease.

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

A New Path Toward Immunotherapy for Alzheimer's

The discovery of the PU.1-CD28 relationship offers a new molecular framework for understanding how microglia can protect the brain. It also strengthens the idea that targeting microglial activity through immune-based therapies could alter the course of Alzheimer's disease.

This research was supported 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, and Clinical and Translational Science Awards.