Despite the therapeutic potential of the link between cholesterol metabolism and Alzheimer's disease (AD) pathogenesis, the mechanisms by which lipid metabolism influence AD pathogenesis remain uncertain. To better understand those mechanisms we have been investigating the role of the transcription factors Nuclear Liver X Receptors (LXRα and LXRβ) which regulate the expression of genes involved in metabolic pathways and transport of cholesterol. LXR ligands are considered one of the most promising targets for prevention and treatment of atherosclerosis and most recently together with ABCA1 have emerged as such for Alzheimer disease. The conventional wisdom is that the therapeutic potential and efficacy of synthetic LXR ligands depends on the transcriptional upregulation of their responsive genes, involved primarily in the regulation of lipid metabolism. Until now, however, LXR ligands for clinical use are not available on the market, nor they have been applied in a clinical trial. The data as outlined above, and the preliminary unpublished results generated in our laboratory, substantiated the design of a drug discovery study for identification of LXR ligands and their systematic evaluation in in vitro and in vivo model systems for AD pathogenesis and progression.Screening a small library of pharmacologically active compounds and off-patent drugs we identified the Proton Pump Inhibitor (PPI) Lansoprazole as an LXR agonist. In secondary screens and counter-screening assays, we confirmed that Lansoprazole directly activates LXR, increases the expression of LXR target genes in brain-derived human cell lines, and increases Abca1 and Apo-E protein levels in primary astrocytes derived from wild type but not LXRα/β double knockout mice. We are proposing further characterization of two PPIs Lansoprazole and Pantoprazole in in vivo model of AD at two ages representing distinct stages in the pathogenesis of AD.