(300 WORDS MAX.) We propose to develop a selective and brain penetrant first-in-human small molecule drug that inhibits the EP2 receptor to treat Alzheimer's disease (AD). The proposed program for AD prevention and treatment will restore the neuroprotective activities of microglia/resident brain macrophages through antagonism of the prostaglandin E2 receptor (EP2). Using both known tool compounds and novel medicinal chemistry to discover and develop a new class of oral drugs, this project highly complements ADDF's current portfolio of drug targets to reduce neuroinflammation.