The Nuclear Receptor PPARγ as a Therapeutic Target for Cerebrovascular and Brain Dysfunction in Alzheimer's Disease

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (alpha, gamma, beta/delta), and synthetic ligands for PPARalpha (fibrates) and PPARgamma (Thiazolidinediones, TZDs) are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARgamma, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARgamma ligands in the treatment of brain disorders such as Alzheimer's disease (AD), leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARgamma agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.