Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Background: In the brain, the type II nuclear receptors LXR and PPAR control cholesterol efflux and inflammation, key processes in Alzheimer disease pathology. Results: Combining the LXR and PPAR agonists decreases the levels of A and inflammation, resulting in improved cognition. Conclusion: The LXR and PPAR agonists complement each other, possibly by modulating microglial function. Significance: Targeting multiple nuclear receptors expands the therapeutic opportunities for AD treatment. Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid (A), which is accompanied by a robust inflammatory response in the brain. Both of these pathogenic processes are regulated by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor (PPAR). Agonists of LXRs have been demonstrated previously to reduce A levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPAR reduce the microglial expression of proinflammatory genes and have also been shown to modulate apoE expression. Here we investigate whether a combination therapy with both LXR and PPAR agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPAR agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate A decreases in the hippocampus. Combined treatment with both agonists provoked a further increase in the expression of apoE and a decrease in the soluble and deposited forms of A. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPAR agonist in the combined treatment paradigm was able to counteract the elevation in plasma triglycerides that is a side effect of LXR agonist treatment. These results suggest that combined LXR/PPAR agonist treatment merits further investigation for the treatment of AD.29035 2159121602National Institutes of Health [R01 AG030482, 5T32NS067431-13]Gail and Elliott Schlang Philanthropic FundCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CAPES [5758/12-2]