Cognitive Enhancement with Rosiglitazone Links the Hippocampal PPARγ and ERK MAPK Signaling Pathways

We previously reported that the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist rosiglitazone (RSG) improved hippocampus-dependent cognition in the Alzheimer's disease (AD) mouse model, Tg2576. RSG had no effect on wild-type littermate cognitive performance. Since extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERKMAPK) is required for many forms of learning and memory that are affected in AD, and since both PPAR gamma and ERK MAPK are key mediators of insulin signaling, the current study tested the hypothesis that RSG-mediated cognitive improvement induces a hippocampal PPAR gamma pattern of gene and protein expression that converges with the ERK MAPK signaling axis in Tg2576 AD mice. In the hippocampal PPAR gamma transcriptome, we found significant overlap between peroxisome proliferator response element-containing PPAR gamma target genes and ERK-regulated, cAMP response element-containing target genes. Within the Tg2576 dentate gyrus proteome, RSG induced proteins with structural, energy, biosynthesis and plasticity functions. Several of these proteins are known to be important for cognitive function and are also regulated by ERK MAPK. In addition, we found the RSG-mediated augmentation of PPAR gamma and ERK2 activity during Tg2576 cognitive enhancement was reversed when hippocampal PPAR gamma was pharmacologically antagonized, revealing a coordinate relationship between PPAR gamma transcriptional competency and phosphorylated ERK that is reciprocally affected in response to chronic activation, compared with acute inhibition, of PPAR gamma. We conclude that the hippocampal transcriptome and proteome induced by cognitive enhancement with RSG harnesses a dysregulated ERK MAPK signal transduction pathway to overcome AD-like cognitive deficits in Tg2576 mice. Thus, PPAR gamma represents a signaling system that is not crucial for normal cognition yet can intercede to restore neural networks compromised by AD.