title: PPARγ recruitment to active ERK during memory consolidation is required for Alzheimer's disease-related cognitive enhancement.
abstract: Cognitive impairment is a quintessential feature of Alzheimer's disease (AD) and AD mouse models. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone improves hippocampus-dependent cognitive deficits in some AD patients and ameliorates deficits in the Tg2576 mouse model for AD amyloidosis. Tg2576 cognitive enhancement occurs through the induction of a gene and protein expression profile reflecting convergence of the PPARγ signaling axis and the extracellular signal-regulated protein kinase (ERK) cascade, a critical mediator of memory consolidation. We therefore tested whether PPARγ and ERK associated in protein complexes that subserve cognitive enhancement through PPARγ agonism. Coimmunoprecipitation of hippocampal extracts revealed that PPARγ and activated, phosphorylated ERK (pERK) associated in Tg2576 in vivo, and that PPARγ agonism facilitated recruitment of PPARγ to pERK during memory consolidation. Furthermore, the amount of PPARγ recruited to pERK correlated with the cognitive reserve in humans with AD and in Tg2576. Our findings implicate a previously unidentified PPARγ-pERK complex that provides a molecular mechanism for the convergence of these pathways during cognitive enhancement, thereby offering new targets for therapeutic development in AD.
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, Departments of Neurology and Internal Medicine, Division of Endocrinology, McCoy Stem Cells and Diabetes Mass Spectrometry Research Laboratory, Sealy Center for Molecular Medicine, and Institute for Translational Science, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Jahrling
authors.forename: Caterina M
authors.initials: CM
authors.lastname: Hernandez
authors.forename: Larry
authors.initials: L
authors.lastname: Denner
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D007276:Injections, Intraventricular; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008875:Middle Aged; D018697:Nootropic Agents / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018697:Nootropic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Alzheimer's; hippocampus; in vitro reconstitution; protein complex; transgenic