Colin Combs

Regulation of β-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor α

Abstract Amyloid deposition within the brains of Alzheimers Disease patients results in the activation of microglial cells and the induction of a local inflammatory response. The interaction of microglia or monocytes with β-amyloid (Aβ) fibrils elicits the activation a complex tyrosine kinase-based signal transduction cascade leading to stimulation of multiple independent signaling pathways and ultimately to changes in proinflammatory gene expression. The Aβ - stimulated expression of proinflammatory genes in myeloid lineage cells is antagonized by the action of a family of ligand-activated nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs). We report that THP-1 monocytes express predominantly PPARγ isoform and lower levels of PPARα and PPARδ isoforms. PPAR mRNA levels are not affected by differentiation of the cells into a macrophage phenotype, nor are they altered following exposure to the classical immune stimulus, lipopolysaccharide. Previous studies have found that PPARγ agonists act broadly to inhibit inflammatory responses. The present study explored the action of the PPARα isoform and found that PPARα agonists inhibited the Aβ-stimulated expression of TNFα and IL-6 reporter genes in a dose-dependent manner. Moreover, the PPARα agonist WY14643 inhibited macrophage differentiation and COX-2 gene expression. However, the PPARα agonists failed to inhibit Aβ-stimulated elaboration of neurotoxic factors by THP-1 cells. These findings demonstrate that PPARα acts to suppress a diverse array of inflammatory responses in monocytes.

Inflammatory Mechanisms in Alzheimer’s Disease: β-Amyloid-Stimulated Proinflammatory Responses are Blocked by PPARγ Agonists

The pathogenesis of Alzheimer’s disease (AD) involves inflammatory processes as evidenced by the presence of abundant reactive microglia and their secretory products in the brain. Moreover, individuals on long-term nonsteroidal anti-inflammatory drug (NSAID) treatments exhibit a dramatic (60%) reduction of risk for AD, reduced symptomatic severity, and delayed progression of the disease. An unappreciated target of NSAIDs action is the transcription factor, peroxisome proliferator activated receptor gamma (PPARγ), whose transcriptional actions are activated upon binding of these drugs, its natural lipid ligands and drugs of the thiazolidinedione class. PPARγ binds to the promoter elements of a number of proinflammatory genes and regulates their expression. Exposure of microglia or monocytes to fibrillar forms of Aβ results in the activation of complex tyrosine kinase-based signaling cascades resulting in a broad range of proinflammatory responses. We report that exposure of monocytes and microglia to PPARγ agonists inhibited the Aβ-stimulated synthesis of the cytokines TNFα and IL-6, and blocked the induction of cyclooxygenase-2 expression. PPARγ agonists blocked the Aβ-mediated secretion of microglial proinflammatory products responsible for neurotoxicity and astrogliosis. Moreover, PPARγ agonists suppressed the Aβ stimulated expression of the complement receptor MAC1 by microglia and blocked macrophage differentiation. These data provide evidence that PPARγ plays a critical role regulating the inflammatory responses of microglia and monocytes to Aβ.