PROJECT SUMMARY Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the sixth leading cause of mortality in the United States and costs $305 billion annually. The strongest genetic risk factor for AD is the ε4 variant of the APOE gene (APOE4), which is found in 60-75% of all AD patients. Despite the importance of apoE4 in AD, the exact role of apoE4 in the pathogenesis of AD remains poorly understood. The proposed studies will fill critical gaps in knowledge by dissecting how different cellular sources of apoE4 modulate tau pathology, neuroinflammation, and neurodegeneration in Alzheimer's disease. It was recently discovered that apoE4 causes increased tau pathology and neurodegeneration. While the detrimental effects of apoE4 on neuronal survival and cognition depend on whether it is produced in neurons or astrocytes, it is unknow if neuronal and astrocytic apoE4 differentially modulate tau pathology and neurodegeneration, which are two critical hallmarks of AD. Additionally, it is unclear if apoE4 can directly induce tau pathology or if the effects of apoE4 on tau are primarily driven by the effects of apoE4 on other pathologies. The proposed studies in this application will determine if apoE4 can directly induce tau pathology and if the effects of apoE4 on tau pathology and neurodegeneration are dependent on the cellular origin of its production. ApoE4 may also play an important role in the activation of neuroinflammatory cells since it leads to increased microgliosis and astrogliosis. Depletion of microglia was also found to reduce the extent of tau pathology and neurodegeneration. Still, it is unknown if removal of neuronal or astrocytic apoE4 will have protective effects on activation of neuroinflammatory cells and on neuroinflammatory cell-mediated and neurodegeneration. In summary, the proposed studies will test the central hypothesis that neuronal and astrocytic apoE4 expression differentially drive tau pathology, activation of neuroinflammatory cells, and subsequent neurodegeneration. The central hypothesis will be investigated using mice that co-express P301S mutant tau and LoxP-floxed human apoE isoforms, in which the human APOE gene can be deleted in astrocytes by expression of GFAP-Cre or in neurons by expression of Syn1-Cre. I will accomplish two aims: (1) Determine if the detrimental effects of apoE4 on tau pathology and neurodegeneration are dependent on its cellular source, and (2) Elucidate the role of different cellular sources of apoE4 on neuroinflammation and neuroinflammatory cell-mediated neurodegeneration. The proposed research will elucidate the fundamental mechanisms of apoE4-related AD pathogenesis and will potentially identify novel targets for future AD therapies.