Alzheimer’s disease (AD) is a devastating brain disorder that affects millions, causing memory loss, cognitive decline, and brain cell death. A hallmark of AD is the accumulation of protein aggregates called tau tangles inside neurons. Tau pathology strongly correlates with cognitive impairment. Microglia, the brain’s immune cells, help protect the brain, but how they respond to tau is not fully understood. ADGRG1 is a protein specifically expressed in microglia. Our preliminary studies show that deleting microglial ADGRG1 worsens tau pathology, increases microglial activation, and leads to greater neuronal loss. In this project, we will study how ADGRG1 helps microglia to eliminate tau by examining brain pathology, neuron and synapse health, and memory-related behavior in a mouse tauopathy model, as well as using human induced pluripotent stem cell–derived microglia and neurons to study tau uptake, clearance, and spread. We aim to uncover the molecular and cellular mechanisms by which ADGRG1 enables microglia to protect the brain from tau spreading. The success of the proposed research could reveal new ways to enhance microglial resilience and identify ADGRG1 as a promising therapeutic target for slowing or preventing AD.
