PROJECT SUMMARY Cerebral ischemia-reperfusion (I/R) is associated with neuroinflammation, mitochondrial dysfunction and oxidative stress, leading to brain injury, function disability and development of Alzheimer’s disease-like pathology and dementia. To fight against I/R induced pathological cascades, numerous neuroprotective strategies and reagents have been identified and studied. However, translation of these neuroprotective strategies and reagents to clinical trials has been unsuccessful, and to date, the tissue plasminogen activator remains to be the only FDA approved drug for treating ischemic stroke. Thus, it is obligatory to identify and validate additional therapeutic targets and reagents for I/R-caused brain disorder. The objective of this project is to validate a novel therapeutic target, FOXO4, as previous data have shown that FOXO4 promotes early tissue inflammation, and downregulation of FOXO4 is associated with reduced cell death and increased neovasculature in ischemic peripheral tissues. Importantly, our pilot data have shown that knockout (KO) of FOXO4 gene dramatically attenuates I/R-caused brain injury and alters numerous genes linked to AD in an ischemic stroke mouse model. Based on these observations, we hypothesize that selective inhibition of FOXO4 activity is protective against ischemic stroke-caused brain injury and AD-like pathology. To test the hypothesis, we will (1) determine the role of FOXO4 in ischemic stroke-induced brain injury using genetically modified mice, (2) study the role of identified FOXO4 inhibitors in treating ischemic stroke-caused brain injury, and (3) understand how loss of FOXO4 confers neuroprotection following ischemic stroke.