The PPAR-γAgonist 15-Deoxy-Δ12,14-ProstaglandinJ2Attenuates Microglial Production of IL-12 Family Cytokines: Potential Relevance to Alzheimer's Disease

Abstract

Accumulation of amyloid-βpeptide (Aβ) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Aβdeposits has been placed in strategies involving immunization against the Aβpeptide. Initial Aβimmunization 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 Aβ. Specifically,CD4+Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβimmunization 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, Aβ1−42synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-γagonist 15-deoxy-Δ12,14-PGJ2(15d-PGJ2) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2suppressed the Aβ-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-γagonists may be effective in modulating the development of AD.