Immune cells in the brain may help slow down Alzheimer's

Alzheimer's

Immune cells in the brain may help slow down Alzheimer's

Using laboratory mouse models of Alzheimer's disease, as well as human brain cells and tissues, an international team of researchers successfully reduced levels of the PU.1 protein, which encourages microglia to express immune regulatory receptors normally found in lymphocytes.
According to NDTV , citing Nature, protective microglia make up a small fraction of the total number of microglia, but their effect is widespread, as they suppress inflammation throughout the brain and help maintain memory and survival in laboratory mice.

Key role of CD28 protein

When the research team removed the CD28 protein from this specific subset of microglia, inflammation worsened and plaque growth increased, confirming that CD28 plays a key role in maintaining the activity of these protective brain cells.

Professor Anne Schaefer, a professor in the Nash 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 Aging, and principal investigator of the study, said, "Microglia are not just destructive responders in Alzheimer's disease; they can also be protective of the brain." She added, "This finding reinforces previous observations about the remarkable plasticity of microglia and their important roles in diverse brain functions."

Professor Alexander Tarakhovsky, professor of immunology, virology and microbiology at Rockefeller University and co-author of the study, noted that "it is remarkable to observe that molecules long known to immunologists for their roles in B and T lymphocytes also regulate the activity of microglia."
This discovery comes at a time when regulatory T cells have gained widespread recognition as key regulators of immunity, highlighting a common logic for immune regulation across cell types. It also paves the way for immunotherapeutic strategies for Alzheimer's disease.

Genetic evidence

This research expands upon previous genetic findings by Professor Allison Gutt, Professor of Genomics and Chair of the Department of Genetics and Genomics at the Icahn School of Medicine and a co-author of the study. Dr. Gutt’s previous work identified a shared genetic variant in the SPI1 gene, which produces PU.1, that is associated with a reduced risk of Alzheimer’s disease.
Dr. Gut stated, "These results provide a mechanistic explanation for why lower PU.1 levels are associated with a reduced risk of Alzheimer's disease."

A new path towards immunotherapy

PU.1 is a protein that binds to specific regions of DNA, helping to control which genes are activated or deactivated. CD28, located on the surface, is a coactivator receptor expressed on T cells, helping to strengthen and maintain an effective immune response.

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 with immunotherapies could alter the course of Alzheimer's disease. Therefore, targeting microglia activity with immunotherapies could pave the way for changing the course of Alzheimer's disease.