PROJECT SUMMARY/ABSTRACT The goal of the proposed studies is to define an IL6 triggered cellular iron sequestration response (CISR) in a mouse model of Alzheimer's Disease (AD). Iron is necessary for growth and survival for all life forms, so cellular iron uptake and sequestration is a mechanism that limits the growth of extracellular bacteria. However, when the CISR is maladaptively activated by chronic neuroinflammation, the resulting iron accumulation can be toxic to the CNS. Toxic iron accumulation and dysregulation have been implicated in AD pathogenesis, and an ongoing phase 2 clinical trial is evaluating an iron chelator in AD patients (NCT03234686). However, understanding the mechanisms leading to iron dysregulation, and the brain cell types affected is likely to lead to a more targeted therapy than iron chelation. Evidence implicating an IL6 induced CISR in AD pathogenesis includes: 1)AD brains have iron dysregulation, with iron accumulation in plaques 2) AD brains have elevated IL6 levels near plaques. overexpressing elevated neurodegeneration Brain as in 3)A transgenic mouse IL6 i n astrocytes has brain iron accumulation. 4)The 5XFAD mouse model of AD has brain iron levels and CISR activation. 5) The iron chelator deferoxamine can ameliorate the phenotype of the AD mode l App/Ps1, another model driven by Aβ deposition. 6) iron dysregulation is also associated with Parkinson's Disease and t he hereditary diseases classified Neurodegenerations with Brain Iron Overload (NBIA). Understanding the role of the IL6 induced CISR AD pathogenesis is thus likely to lead to novel therapeutics for patients suffering from this disease.