01/20/2026
Spatial transcriptomics reveals that microglia play more nuanced roles in Alzheimer’s disease than previously understood, including distinct states associated with neuroprotection.
A new study published in Nature, drawing on mouse models and human post-mortem tissue, identifies a microglial subpopulation marked by low expression of PU.1 (SPI1) and activation of a lymphoid-like gene program, including receptors such as CD28 and CD5. These PU.1-low, CD28-positive microglia localize near amyloid plaques and are associated with reduced neuroinflammation and reduced amyloid and tau pathology in Alzheimer’s disease models.
The study further shows that lowering PU.1 expression in microglia shifts them toward this protective state, while microglia-specific deletion of CD28 leads to increased inflammation and plaque burden, underscoring a functional role for lymphoid-type signaling programs in microglial regulation.
Using the MERSCOPE platform, researchers were able to resolve these findings directly within intact mouse and human brain tissue. Spatial analysis made it possible to:
•Map PU.1-low, CD28-positive microglia at single-cell resolution within disease-relevant tissue regions
•Quantify lymphoid gene programs, including CD28, CD5, and Lck, in situ rather than inferring them from dissociated cells
•Reveal how protective microglia cluster in niche environments around amyloid plaques and interact with astrocytes and neurons
Together, these spatial insights help explain why genetic variation in SPI1 is linked to delayed disease onset and milder progression, and they point toward strategies that aim to promote protective microglial states rather than broadly suppress immune activity.
Read the paper: https://hubs.ly/Q03-thGy0
Image description: Representative MERFISH images of plaque-associated and distal microglia in an Alzheimer’s disease mouse model. Image source: Nature.
