Protective Brain Immune Cells: The Key to Slowing Alzheimer's Disease Progression

Scientists have discovered specialized immune cells in the brain that play a crucial role in slowing Alzheimer's disease progression. These microglia function by reducing inflammation and inhibiting the spread of harmful proteins, potentially safeguarding memory and overall brain health, which opens promising avenues for new therapeutic approaches.

In research published in Nature on November 5, investigators identified that microglia with reduced levels of the transcription factor PU.1 and elevated expression of CD28 receptor effectively decrease brain inflammation.

These specialized microglia additionally impede the accumulation of amyloid plaques and prevent the propagation of toxic tau proteins, both recognized as significant indicators of Alzheimer's disease.

PU.1 operates as a protein that attaches to specific DNA segments, regulating gene activation and silencing. CD28, located on T cell surfaces, functions as a signaling receptor facilitating immune cell activation and intercellular communication.

Through experiments with Alzheimer's mouse models and analysis of human brain cells and tissue samples, researchers demonstrated that decreasing PU.1 levels promotes microglia to express immune-regulating receptors typically associated with lymphoid cells.

Despite comprising only a small fraction of total microglia, these protective cells exert broad influence: they inhibit inflammation throughout the brain and contribute to memory preservation and extended survival in mice.

When researchers eliminated CD28 from this particular microglial subgroup, inflammation intensified and plaque formation accelerated, confirming CD28's essential role in maintaining these brain-protective cells' functionality.

"Microglia are not simply destructive responders in Alzheimer's disease -- they can become the brain's protectors," explained 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," Anne further noted.

"It is remarkable to see that molecules long known to immunologists for their roles in B and T lymphocytes also regulate microglial activity," stated 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," Alexander added.

This research builds upon previous genetic discoveries 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 earlier work identified a common genetic variant in SPI1 (the gene producing PU.1) associated with reduced Alzheimer's disease risk.

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

The identification of the PU.1-CD28 relationship presents a novel molecular framework for understanding how microglia protect the brain. This discovery reinforces the potential for targeting microglial activity through immune-based therapies to potentially alter Alzheimer's disease progression.