AGING NEUROSCIENCE REVIEW ARTICLE

Takeda pharmaceuticals), which do not share the hepatotoxic pro-fi le of troglitazone (Scheen, 2001), were released and continue to be prescribed today in the management of type II diabetes. In more recent years, the focus on PPARγ has intensifi ed, as new ligands and novel biological roles have emerged for the receptor, particu-larly for its therapeutic potential in neurodegenerative disorders, such as Alzheimer’s disease (AD). Previous excellent reviews have highlighted the benefi ts of PPARγ activation for the treatment of AD (Landreth et al., 2008; Jiang et al., 2008). The present review incorporates both supportive and contradictory evidence for the benefi cial role of PPARγ ligands on affl icted neuronal, glial, and notably, cerebrovascular networks in AD. Gaps in our knowledge are addressed, and the value of PPARγ agonists as future AD thera-peutics is discussed, in view of the latest clinical trials. MECHANISM OF ACTION Peroxisome proliferator-activated receptors are members of the nuclear receptor superfamily, an evolutionarily conserved family of receptors that also includes the thyroid, estrogen, and gluco-corticoid receptors, each playing vital roles in development, endo-crine signaling and metabolism. There are 48 nuclear receptors in humans, and PPARs belong to the class of ligand-dependent recep-tors (24) that convey a variety of hormonal and metabolic signals directly to the genome by activating or repressing transcription via their ligand-binding (LBD) and DNA-binding (DBD) domains (Nagy and Schwabe, 2004). The remaining receptors comprise the orphan receptors, for which ligands are unknown or may not exist (‘true orphans’) or are only recently being discovered (‘adopte