Metabolic mechanisms of cognitive decline in aging and AD mediated by inflammatory PGE2 signaling Project Summary Aging is characterized by the development of maladaptive immune responses that promote cognitive decline and Alzheimer’s disease (AD). We recently identified the inflammatory lipid messenger prostaglandin E2 (PGE2), signaling through its EP2 receptor, as a major driver of age-associated inflammation and cognitive decline. Genetic deletion of the EP2 receptor in myeloid cells was sufficient to prevent systemic and brain inflammation and cognitive decline in aging mice. Myeloid EP2 deletion rescued healthy immune cell responses by restoring glucose flux and downstream mitochondrial respiration in aging macrophages and microglia. We also made the surprising observation that peripheral inhibition of EP2 signaling with a non-brain penetrant EP2 antagonist phenocopied the effect of pan-myeloid EP2 genetic deletion. These data suggest that peripheral inhibition of pro-inflammatory PGE2 signaling is sufficient to restore healthy hippocampal function in aging mice. In this proposal, we will build on these initial findings and define how metabolically reprogrammed myeloid cells in the periphery can elicit effects beyond the blood-brain barrier (BBB) that reverse changes in hippocampal function in models of aging and AD pathology. We will test the hypothesis that the beneficial immune-metabolic effects of EP2 inhibition on myeloid cells in the periphery are transmitted from the blood to the cerebral endothelium and then to astrocytes, leading to improved astrocytic support of neurons. We will employ preclinical models of aging and mutant APP lines, targeted metabolomics and transcriptomics to understand how improving peripheral myeloid energy metabolism leads to beneficial effects beyond the blood brain barrier. We will test whether peripheral EP2 immune blockade, by reprogramming circulating blood, will improve endothelial function. We will then test whether astrocytes, whose foot processes envelop the capillary bed are in turn functionally improved. As astrocytes support neuronal metabolism, we hypothesize that peripheral EP2 inhibition will improve astrocytic support of neurons, leading to improved cognitive function in models of aging and AD.