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

Abstract

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.

Keywords: arterial reactivity; brain metabolism; cerebral blood flow; inflammation; oxidative stress; pioglitazone; spatial memory; vascular fibrosis.

Figure 1

Anti-inflammatory effects of PPARγ agonists in transgenic mouse models of AD or of the cerebrovascular pathology of the disease. (A) Pioglitazone (Pio) and ibuprofen (Ibu) attenuated GFAP and iNOS expression in astrocytes of the hippocampus (HC) and frontal cortex (FC) of treated APPV717I mice. Bar, 50 μm. Reproduced with kind permission from Heneka et al. (2005) and Elsevier. (B) Pioglitazone countered microglial activation in TGF mice (T+) relative to age-matched controls (T−), as seen by the shrinking of the cell soma in animals treated for 2 months starting at 2 months of age. Bar, 50 μm. Reproduced with permission from Lacombe et al. (2004) and BioMed Central publisher.

Figure 2

(A) Genetic inactivation of PPARγ in cerebral arterioles (L/+) leads to an increase in O₂^·− content relative to control vessels (+/+), as detected with dihydroethidine fluorescence. Bar, 20 μm. Reproduced with permission from Beyer et al. (2008) and Wolters Kluwer. (B) Pioglitazone (pio) rescued cerebrovascular dilatations to acetylcholine (ACh) and the neurovascular coupling response to whisker stimulation in aged APP mice. ●, wild-type (WT); ○, treated WT; ▲, APP; △, treated APP. Reproduced from Nicolakakis et al. (2008). (C) Pioglitazone restored CBF in the parietal and frontal lobes of AD patients in single photon emission computed tomography (SPECT) studies. Reproduced with generous permission from Sato et al. (2009) and Elsevier.

Figure 3

PPARγ activation could rescue afflicted vascular, glial, and neuronal compartments in the AD brain. Transcriptional suppression of inflammatory, oxidative, and fibrotic pathways would reduce tissue injury and reinstate adequate substrate delivery by the cerebral circulation. TZDs capable of passing the BBB could upregulate anti-apoptotic factors in neurons, re-sensitize cells to insulin and restore glucose utilization. The potential to counter amyloidogenesis and τ hyperphosphorylation could be disease-modifying, but requires further empirical support and confirmation in patients.