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| Inflammatory mechanisms in Alzheimer's disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPAR gamma agonists |
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| Author(s): Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE |
| Source: JOURNAL OF NEUROSCIENCE Volume: 20 Issue: 2 Pages: 558-567 Published: JAN 15 2000 |
| Times Cited: 243 References: 73 |
| Abstract: Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid fibrils within the brain and the subsequent association and phenotypic activation of microglial cells associated with the amyloid plaque. The activated microglia mount a complex local proinflammatory response with the secretion of a diverse range of inflammatory products. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in reducing the incidence and risk of AD and significantly delaying disease progression. A recently appreciated target of NSAIDs is the ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma). PPAR gamma is a DNA-binding transcription factor whose transcriptional regulatory actions are activated after agonist binding. We report that NSAIDs, drugs of the thiazolidinedione class, and the natural ligand prostaglandin J2 act as agonists for PPAR gamma and inhibit the beta-amyloid-stimulated secretion of proinflammatory products by microglia and monocytes responsible for neurotoxicity and astrocyte activation. The activation of PPAR gamma also arrested the differentiation of monocytes into activated macrophages. PPAR gamma agonists were shown to inhibit the beta-amyloid-stimulated expression of the cytokine genes interleukin-6 and tumor necrosis factor alpha. Furthermore, PPAR gamma agonists inhibited the expression of cyclooxygenase-2. These data provide direct evidence that PPAR gamma plays a critical role in regulating the inflammatory responses of microglia and monocytes to beta-amyloid. We argue that the efficacy of NSAIDs in the treatment of AD may be a consequence of their actions on PPAR gamma rather than on their canonical targets the cyclooxygenases. Importantly, the efficacy of these agents in inhibiting a broad range of inflammatory responses suggests PPAR gamma agonists may provide a novel therapeutic approach to AD. |
| Document Type: Article |
| Language: English |
| Reprint Address: Landreth, GE (reprint author), Case Western Reserve Univ, Sch Med, Alzheimers Res Lab, Dept Neurosci, E504,10900 Euclid Ave, Cleveland, OH 44106 USA |
Addresses:
1. Case Western Reserve Univ, Sch Med, Alzheimers Res Lab, Dept Neurosci, Cleveland, OH 44106 USA
2. Case Western Reserve Univ, Sch Med, Alzheimers Res Lab, Dept Neurol, Cleveland, OH 44106 USA |
| Publisher: SOC NEUROSCIENCE, 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA |
| Subject Category: Neurosciences |
| IDS Number: 277JC |
| ISSN: 0270-6474 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |