PROJECT SUMMARY/ABSTRACT Tau pathology is central to the development of Alzheimer’s disease (AD) and its clinical progression, hence current therapeutic efforts are directed at reducing tau burden in the brain by immunotherapy. The initial seeding and deposition of tau is associated with an early inflammatory response, in both human disease and mouse models of AD. The immune system responds rapidly to the accumulation of tau and other aggregated proteins, in order to clear them from the brain and prevent further immune activation. However, if clearance is unsuccessful, the accumulation of aggregated proteins will likely lead to excessive inflammation, and paradoxically, more tau spreading and accumulation. This complex relationship between tau pathology and inflammation is still not fully characterized. We identified the transcription factor interferon regulatory factor 5 (IRF5) as a new mediator of microglia activation in response to pathological tau. We found that IRF5 is activated, i.e. nuclear-localized, in microglia after stimulation with pathological tau, and IRF5 expression is increased in brain tissue from AD patients as compared to healthy donors. Further, aged mice lacking IRF5 showed increased accumulation of soluble tau. Together, these data suggest a new role for IRF5 in microglia immunosurveillance of aggregated, pathological tau. The premise of this application is that IRF5-mediated signaling in microglia is a critical step in regulating tau accumulation. In this proposal, we will 1) Test the hypothesis that IRF5 is required for immunosurveillance of pathological tau in the brain, 2) Determine whether therapeutic inhibition of IRF5 protects P301S mice from disease onset, progression and neurodegeneration, and 3) Determine the mechanism(s) by which IRF5 participates in the immune response against pathological tau. Successful completion of these studies will 1) identify a new factor – IRF5 – that contributes to immunosurveillance of pathogenic stimuli in the brain and 2) determine whether IRF5 is a viable therapeutic target for AD and tauopathies.