PPARγ recruitment to active ERK during memory consolidation is required for alzheimer's disease-related cognitive enhancement

Jordan B. Jahrling, Caterina M. Hernandez, Larry Denner, Kelly T. Dineley

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4054-4063
Number of pages10
JournalJournal of Neuroscience
Volume34
Issue number11
DOIs
StatePublished - 2014

Keywords

  • Alzheimer's
  • Hippocampus
  • In vitro reconstitution
  • Protein complex
  • Transgenic

ASJC Scopus subject areas

  • Neuroscience(all)

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