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

Abstract

We previously reported that the peroxisome-proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone (RSG) improved hippocampus-dependent cognition in the Alzheimer's disease (AD) mouse model, Tg2576. RSG had no effect on wildtype littermate cognitive performance. Since ERK MAPK is required for many forms of learning and memory that are affected in AD, and since both PPARγ and ERK MAPK are key mediators of insulin signaling, the current study tested the hypothesis that RSG-mediated cognitive improvement induces a hippocampal PPARγ pattern of gene and protein expression that converges with the ERK MAPK signaling axis in Tg2576 AD mice. In the hippocampal PPARγ transcriptome, we found significant overlap between PPRE-containing PPARγ target genes and ERK-regulated, CRE-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 PPARγ and ERK2 activity during Tg2576 cognitive enhancement was reversed when hippocampal PPARγ was pharmacologically antagonized, revealing a coordinate relationship between PPARγ transcriptional competency and pERK that is reciprocally affected in response to chronic activation, compared to acute inhibition, of PPARγ. 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, PPARγ represents a signaling system that is not crucial for normal cognition yet can intercede to restore neural networks compromised by AD.

Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice

“…Several studies using various treatment paradigms with PPAR␥ agonists observed decreases in soluble A␤ species (45,46), plaques (47,48) or both (27,36,49,50), and others reported decreased intracellular A␤ (51,52). However, there were also cases where PPAR␥ agonists exhibited no measurable effect on A␤ pathology (53)(54)(55). LXR agonists have had a similarly mixed success since 2005, when Koldamova et al (11) reported that TO901317 was able to reduce soluble A␤ levels in APP23 mice .…”

“…LXR (9, 13, 18, 20 -24) and PPAR␥ (27,36,46,48,50,52,55,59,60) agonists have been reported to ameliorate memory deficits using a variety of tests in a range of mouse models. It should be noted, however, that Nicolakakis et al (53), Masciopinto et al (59), and Papadopoulos et al (54) reported no behavioral improvements after treating mice with pioglitazone.…”

Biomarker Discovery for Early Detection of Hepatocellular Carcinoma in Hepatitis C–infected Patients

“…Bound proteins were eluted by incubating beads with 200 l of elution buffer (8 M urea and 2% CHAPS) for 15 min on a rotator. This was repeated three times such that the total volume after enrichment of 1 ml serum was 600 l. The enrichment protocol reduced high-abundance proteins by 97% and was found to be reproducible over a number of patient samples (recovery coefficient of variation Ͻ 5%, n ϭ 12) and was thus seen as an appropriate strategy to incorporate into two-dimensional DIGE and 18 O/ 16 O studies. Protein Processing and Labeling-To remove salts and other contaminants and to improve spot resolution, enriched serum samples from the ProteoMiner were cleaned using an Ettan 2-D Cleanup Kit and the protein pellets were resuspended in ice-cold DIGE-specific lysis buffer (30 mM Tris, 8 M urea, 2% CHAPS, pH 8.5 buffer).…”

“…Differential Stable Isotope Labeling- 18 O/ 16 O differential stable isotope labeling was performed as described elsewhere (15)(16)(17)(18), with slight modifications. Briefly, 100 g each of HCV and HCC serum samples, both crude and ProteoMiner enriched, were denatured with 8 M GdmCl, reduced with 10 mM DTT for 30 min, alkylated with 30 mM iodoacetamide for 2 h at 37°C, digested with trypsin (1:50 enzymeto-protein ratio), diluted 10-fold with 50 mM ammonium bicarbonate, and incubated at 37°C for 24 h. Trypsin was deactivated by incubating samples at 95°C for 10 min and adding 12 l of 0.1% TFA to each sample.…”

“…DeCyder software was used to identify differentially expressed proteins and spots picked, and MALDI-MS/MS was used to determine that ApoA1 was down-regulated by 22% (p < 0.004) in HCC relative to HCV. Differential expression quantified via two-dimensional difference gel electrophoresis was confirmed by means of 18 …”