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Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha
C K Combs1, P Bates, J C Karlo
1Alzheimer Research Laboratory E504, Department of Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Abstract:
Amyloid deposition within the brains of Alzheimer's Disease patients results in the activation of microglial cells and the induction of a local inflammatory response. The interaction of microglia or monocytes with beta-amyloid (A beta) 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 A beta-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 PPAR gamma isoform and lower levels of PPAR alpha and PPAR delta 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 PPAR gamma agonists act broadly to inhibit inflammatory responses. The present study explored the action of the PPAR alpha isoform and found that PPAR alpha agonists inhibited the A beta-stimulated expression of TNFalpha and IL-6 reporter genes in a dose-dependent manner. Moreover, the PPAR alpha agonist WY14643 inhibited macrophage differentiation and COX-2 gene expression. However, the PPAR alpha agonists failed to inhibit A beta-stimulated elaboration of neurotoxic factors by THP-1 cells. These findings demonstrate that PPAR alpha acts to suppress a diverse array of inflammatory responses in monocytes.
Insights
Peroxisome proliferator-activated receptor alpha (PPARα) agonists suppress inflammatory gene expression in monocytes stimulated by beta-amyloid (Aβ). However, PPARα agonists do not inhibit the release of neurotoxic factors, indicating a specific role in modulating inflammation.
Area of Science:
- Neuroinflammation
- Molecular Biology
- Immunology
Background:
- Alzheimer's Disease (AD) involves brain amyloid deposition, activating microglia and causing inflammation.
- Beta-amyloid (Aβ) fibrils trigger signaling cascades in myeloid cells, increasing pro-inflammatory gene expression.
- Peroxisome proliferator-activated receptors (PPARs) antagonize this inflammatory gene expression.
Purpose of the Study:
- To investigate the role of PPAR alpha (PPARα) in modulating inflammatory responses in monocytes exposed to Aβ.
- To determine if PPARα agonists inhibit Aβ-stimulated inflammatory gene expression and neurotoxic factor elaboration.
Main Methods:
- THP-1 monocytes were used to study PPAR isoform expression.
- Cells were exposed to Aβ fibrils and PPARα agonists (e.g., WY14643).
- Reporter gene assays measured TNFα and IL-6 expression; COX-2 gene expression and neurotoxic factor release were also assessed.
Main Results:
- THP-1 monocytes predominantly express PPARγ, with lower levels of PPARα and PPARδ.
- PPARα agonists dose-dependently inhibited Aβ-stimulated TNFα and IL-6 reporter gene expression.
- WY14643 inhibited macrophage differentiation and COX-2 expression but not Aβ-stimulated neurotoxic factor release.
Conclusions:
- PPARα plays a significant role in suppressing diverse inflammatory responses in monocytes.
- PPARα activation inhibits key inflammatory mediators like TNFα and IL-6 in response to Aβ.
- PPARα's inability to block neurotoxic factor release suggests a targeted anti-inflammatory mechanism in AD pathogenesis.