Using Alzheimer's mouse models, human cells, and human brain tissue, researchers showed that reducing PU.1 promotes the expression of lymphoid immune regulatory receptor proteins on microglia. Although these neuroprotective microglia are present in small numbers, they exert a brain-wide suppressive effect on inflammation and protect cognitive function and survival in mice. Deleting CD28 from this small microglia subpopulation enhanced inflammation and accelerated plaque growth, underscoring the key role of CD28 in the protective activity of microglia.
“Microglia are not just destructive cells in Alzheimer’s – they can also protect the brain,” said Anne Schaefer, lead author of the study and head of the research project. “This finding expands on our previous observations of the remarkable plasticity of microglia and their important role in various brain functions. It also underscores the crucial importance of international collaboration for scientific progress.”
“It is remarkable that molecules long known to immunologists for their role in B and T lymphocytes also regulate microglial activity,” added Alexander Tarakhovsky. “This discovery comes at a time when regulatory T cells have gained significant recognition as central regulators of immunity, illustrating a common logic of immune regulation across different cell types. It also paves the way for immunotherapeutic strategies against Alzheimer's disease.”
The study builds on the groundbreaking genetic work of Alison Goate, one of the study’s lead authors. She identified a common variant in the SPI1 gene – the gene that encodes PU.1 – that is associated with a reduced risk of Alzheimer's. “These findings provide a mechanistic explanation for why lower PU.1 levels are associated with a lower risk of Alzheimer's,” Goate said.
The discovery of the PU.1–CD28 axis creates a molecular framework for understanding protective microglial states and highlights the potential of microglia-targeting immunotherapies to influence the course of Alzheimer's disease.
Journal
Nature
DOI
