Newly Identified Microglia Subtype Linked to Reduced Alzheimer’s Risk, Offering Potential Therapy Target
Cologne, Germany – Researchers at the Max Planck Institute for Biology of Aging have identified a protective subtype of microglia, the brain’s resident immune cells, that exhibits a unique gene expression profile associated with a lower risk of Alzheimer’s disease. The finding, published May 8, 2024, in Nature, reveals a critical link between the PU.1 protein, lymphoid gene expression, and microglia function, perhaps opening new avenues for immunotherapies targeting the disease.
Alzheimer’s disease affects over 6.7 million Americans and is a leading cause of death, with numbers projected to rise dramatically as the population ages. While current treatments primarily address symptoms, this research offers a potential pathway toward disease modification by harnessing the brain’s own immune defenses. The team’s findings pinpoint a specific microglial state characterized by the expression of lymphoid genes – typically associated with the lymphatic system – that appears to actively protect against the advancement of Alzheimer’s pathology.
The study centers on the PU.1 protein, a key regulator of immune cell development. Researchers found that lower levels of PU.1 in microglia correlate with increased expression of these protective lymphoid genes and a corresponding reduction in Alzheimer’s risk.This connection was revealed through detailed analysis of gene expression in microglia and experiments demonstrating the functional impact of manipulating PU.1 levels.
“These results provide a mechanistic explanation for why lower PU.1 levels are associated with a reduced risk of Alzheimer’s disease,” explained Dr. Anne Goate, a lead researcher on the project.the team identified a specific molecular pathway – the PU.1-CD28 axis – that governs this protective microglial state.
The discovery provides a molecular framework for understanding how microglia can be modulated to fight Alzheimer’s. Researchers believe that therapies designed to promote this protective microglial state, potentially through microglia-targeted immunotherapies, could alter the course of the disease. Further research is underway to explore the therapeutic potential of this approach.
Original publication: Ayata, Crowley, Challman et al., Lymphoid gene expression supports neuroprotective microglia function. Nature, DOI: 10.1038/s41586-025-09662-z.
Scientific contact: Anne Schaefer, Director Max Planck Institute for Biology of Aging, aschaefer@age.mpg.de.
