Discovery of Neuroprotective Microglia Subtype Offers New Hope for Alzheimer's Treatment

In a study published on November 5, 2025, in Nature, researchers from the Icahn School of Medicine at Mount Sinai, in collaboration with international partners, have identified a distinct subtype of microglia—immune cells in the brain—that exhibit neuroprotective properties in Alzheimer's disease. (mountsinai.org)

This discovery reveals that microglia with reduced expression of the transcription factor PU.1 and increased expression of the receptor CD28 can limit neuroinflammation and slow the accumulation of amyloid plaques and neurotoxic tau proteins, hallmark features of Alzheimer's disease. Targeting the PU.1-CD28 axis in microglia presents a novel therapeutic approach to mitigate disease progression.

Alzheimer's disease is the leading cause of dementia worldwide, characterized by cognitive decline due to the accumulation of amyloid-beta plaques and tau protein tangles, leading to neurodegeneration. Microglia, the brain's resident immune cells, can both protect neurons by clearing harmful debris and contribute to neuroinflammation and neuronal damage. Understanding the mechanisms that govern microglial behavior is crucial for developing targeted therapies.

The research team utilized 5xFAD mouse models, genetically engineered to develop amyloid plaques similar to those in human Alzheimer's disease. By manipulating PU.1 expression levels, they observed changes in microglial behavior and subsequent effects on amyloid plaque formation and tau protein propagation. Lowering PU.1 expression in microglia led to increased CD28 expression, resulting in a subset of microglia that exhibited reduced pro-inflammatory responses. These PU.1^low^ CD28^+^ microglia were more effective in compacting amyloid plaques and resisting the spread of tau proteins. Additionally, these changes were associated with preserved synaptic structure and function, as well as improved cognitive performance in the mice.

Dr. Jessica M. Crowley, co-first author and MD/PhD student at the Icahn School of Medicine at Mount Sinai, emphasized the significance of the findings:

"Our study reveals a previously unrecognized microglial state that can be harnessed to protect neurons in Alzheimer's disease. By targeting the PU.1-CD28 pathway, we may develop therapies that not only reduce amyloid and tau pathology but also preserve cognitive function."

The identification of PU.1^low^ CD28^+^ microglia opens new therapeutic avenues. Modulating the PU.1-CD28 pathway could enhance the neuroprotective functions of microglia, potentially slowing or halting the progression of Alzheimer's disease. This approach differs from current treatments that primarily focus on reducing amyloid-beta levels without addressing the inflammatory component of the disease.

Understanding the mechanisms that enable microglia to adopt a neuroprotective state could have implications beyond Alzheimer's disease, potentially applicable to other neurodegenerative diseases where neuroinflammation plays a critical role, such as Parkinson's disease and multiple sclerosis.

The identification of a neuroprotective microglia subtype characterized by reduced PU.1 and increased CD28 expression marks a significant advancement in Alzheimer's disease research. This discovery not only enhances our understanding of the disease's pathology but also opens new avenues for therapeutic development aimed at modulating the brain's immune response to combat neurodegeneration.