Accumulation of amyloid-beta peptide (Abeta) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Abeta deposits has been placed in strategies involving immunization against the Abeta peptide. Initial Abeta immunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Abeta. Specifically, CD4(+) Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Abeta immunization in the treatment of AD. Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Abeta(1-42) synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-gamma agonist 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ(2) suppressed the Abeta-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-gamma agonists may be effective in modulating the development of AD.