Peroxisome proliferator-activated receptor (PPAR)β/δ, a possible nexus of PPARα- and PPARγ-dependent molecular pathways in neurodegenerative diseases: Review and novel hypotheses

Peroxisome proliferator-activated receptors (PPARα, -β/δ and -γ) are lipid-activated transcription factors. Synthetic PPARα and PPARγ ligands have neuroprotective properties. Recently, PPARβ/δ activation emerged as the focus of a novel approach for the treatment of a wide range of neurodegenerative diseases. To fill the gap of knowledge about the role of PPARβ/δ in brain, new hypotheses about PPARβ/δ involvement in neuropathological processes are requested. In this paper, we describe a novel hypothesis, claiming the existence of tight interactions between the three PPAR isotypes, which we designate the "PPAR triad". We propose that PPARβ/δ has a central control of the PPAR triad. The majority of studies analyze the regulation only by one of the PPAR isotypes. A few reports describe the mutual regulation of expression levels of all three PPAR isotypes by PPAR agonists. Analysis of these studies where pairwise interactions of PPARs were described allows us to support the existence of the PPAR triad with central role for PPARβ/δ. In the present review, we propose the hypothesis that in a wide range of brain disorders, PPARβ/δ plays a central role between PPARα and PPARγ. Finally, we prove the advantages of the PPAR triad concept by describing hypotheses of PPARβ/δ involvement in the regulation of myelination, glutamate-induced neurotoxicity, and signaling pathways of reactive oxygen species/NO/Ca(2+).