Dr. Liddelow’s project investigates how astrocytes at the brain’s borders translate immune signals from the body into inflammatory responses that shape Alzheimer’s disease (AD) pathology. Astrocytes are traditionally viewed as support cells, but recent work—including discoveries from this lab—has identified distinct reactive states that can either exacerbate or potentially constrain neurodegeneration. In particular, the Dr. Liddelow’s team has characterized interferon-responsive reactive astrocytes and shown that these cells are present in human AD brain tissue.
The central hypothesis is that astrocytes located at the brain’s surface act as immune sentinels, sensing interferon signals generated during peripheral inflammation and adopting antigen-presenting functions that influence interactions with T cells and microglia. Depending on the type of interferon signaling engaged, astrocytes may either amplify damaging inflammation or promote protective immune balance.
To test this, the team will define how interferon-responsive astrocytes expand and regulate T cell activity using advanced gene-editing platforms and co-culture systems. They will determine how different interferon pathways program astrocytes into distinct functional states and identify gene targets or existing FDA-approved compounds that shift astrocytes toward more protective profiles. Finally, they will validate key pathways in Alzheimer’s mouse models to determine whether modifying astrocyte interferon signaling alters T cell infiltration, microglial activation, amyloid and tau burden, and cognitive outcomes.
In close collaboration with consortium partners, the Liddelow lab will integrate shared mouse cohorts, single-cell datasets, and spatial profiling platforms to examine how astrocytes interact with microglia, border macrophages, and infiltrating T cells. These coordinated efforts will allow the team to identify convergent immune pathways that could be prioritized for translational targeting. Ultimately, this project seeks to determine whether rebalancing astrocyte-driven immune responses can improve resilience in AD.
