Using Alzheimer’s mouse models, human cells, and human brain tissue, the researchers demonstrated that lowering PU.1 promotes the expression of lymphoid immunoregulatory receptor proteins on microglia. Despite being present in small numbers, these neuroprotective microglia exert a brain-wide suppressive impact on inflammation and protect cognitive function and survival in mice. Deleting CD28 from this small subset of microglia amplified inflammation and accelerated plaque growth, highlighting CD28’s key role in protective microglial activity.
“Microglia are not simply destructive responders in Alzheimer’s disease— they can become the brain’s protectors,” said Anne Schaefer, the senior author of the paper and leader of the project. “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. “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.”
The study builds on pioneering genetic work by Alison Goate, a senior co-author of the study, who identified a common variant in SPI1 —the gene encoding PU.1—as being associated with reduced Alzheimer’s risk. “These results provide a mechanistic explanation for why lower PU.1 levels are linked to reduced Alzheimer’s risk,” said Goate.
The discovery of the PU.1–CD28 axis establishes a molecular framework for understanding protective microglial states and highlights the potential of microglia-targeted immunotherapies to modify the course of Alzheimer’s disease.
Nature
Experimental study
Human tissue samples
Lymphoid gene expression supports neuroprotective microglia function
5-Nov-2025