PPARs in Alzheimer's Disease

Abstract

Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.

Figure 1

Effects of PPARγ on Aβ metabolism. Excessive production or insufficient clearance of Aβ results in its aggregation and finally in the formation of amyloid plaques. This process induces the activation of microglia as well as astrocytes which respond with the secretion of proinflammatory molecules like NO, cytokines, and prostaglandins developing the inflammatory phenotype of AD. In addition, cytokines are able to increase BACE1 activity thereby stimulating Aβ production. PPARγ agonists are able to abate both effects by either transrepress the production of proinflammatory molecules or directly interfere with the binding of PPARγ to a PPRE in the BACE1 gene promoter.