Newly Discovered microglia Subtype Linked to alzheimer’s Disease Protection, Offering Potential Immunotherapy Target
Cologne, Germany – Researchers at teh Max Planck Institute for Biology of aging have identified a specific subtype of microglia – the brain’s resident immune cells – that exhibits protective functions against Alzheimer’s disease. The revelation, published today in Nature, reveals a molecular mechanism linking lower levels of the PU.1 protein to this protective microglial state and opens avenues for developing targeted immunotherapies.
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 to modify the disease’s progression by harnessing the brain’s own immune defenses. The team’s findings centre on the interplay between PU.1 and the CD28 receptor on microglia, revealing a previously unknown “lymphoid gene expression” pattern associated with neuroprotection.
The study demonstrates that microglia expressing higher levels of CD28, and consequently lower levels of PU.1, are more effective at clearing amyloid plaques – a hallmark of Alzheimer’s disease – and promoting neuronal health. “These results provide a mechanistic explanation for why lower PU.1 levels are associated with a reduced risk of Alzheimer’s disease,” explained Dr. Alison Goate,a lead researcher on the project.
Researchers found this protective microglial state is characterized by the expression of genes typically associated with lymphoid cells, suggesting a surprising connection between the brain’s immune system and the body’s broader immune response. This discovery provides a molecular framework for understanding how to promote these beneficial microglial states and highlights the potential of microglia-targeted immunotherapies to alter the course of Alzheimer’s disease.
The research was led by Anne Schaefer, Director of the Max Planck Institute for Biology of Aging, and involved contributions from Ayata, Crowley, Challman, and others. Further details can be found in the original publication: Ayata, Crowley, Challman et al., Lymphoid gene expression supports neuroprotective microglia function. Nature, DOI: 10.1038/s41586-025-09662-z.
