title: Cognitive enhancement with rosiglitazone links the hippocampal PPARγ and ERK MAPK signaling pathways.
abstract: We previously reported that the peroxisome proliferator-activated receptor γ (PPARγ) 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 (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 peroxisome proliferator response element-containing PPARγ 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 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 phosphorylated ERK that is reciprocally affected in response to chronic activation, compared with 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.
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Denner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rodriguez-Rivera
authors.forename: Sigmund J
authors.initials: SJ
authors.lastname: Haidacher
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Jahrling
authors.forename: J Russ
authors.initials: JR
authors.lastname: Carmical
authors.forename: Caterina M
authors.initials: CM
authors.lastname: Hernandez
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rovshan G
authors.initials: RG
authors.lastname: Sadygov
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Starkey
authors.forename: Heidi
authors.initials: H
authors.lastname: Spratt
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Luxon
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Wood
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000502:physiology; D003213:Conditioning, Psychological; D004597:Electroshock; D005239:Fear; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D007276:Injections, Intraventricular; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018697:Nootropic Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D016133:Polymerase Chain Reaction; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology*; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000494:pharmacology*; D059467:Transcriptome / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D018697:Nootropic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone