TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys

Mychael V. Lourenco, Julia R. Clarke, Rudimar L. Frozza, Theresa R. Bomfim, Letícia Forny-Germano, André F. Batista, Luciana B. Sathler, Jordano Brito-Moreira, Olavo B. Amaral, Cesar A. Silva, Léo Freitas-Correa, Sheila Espírito-Santo, Paula Campello-Costa, Jean Christophe Houzel, William L. Klein, Christian Holscher, José B. Carvalheira, Aristobolo M. Silva, Lício A. Velloso, Douglas P. MunozSergio T. Ferreira*, Fernanda G. De Felice

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR-/- and TNFR1-/- mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.

Original languageEnglish (US)
Pages (from-to)831-843
Number of pages13
JournalCell Metabolism
Volume18
Issue number6
DOIs
StatePublished - Dec 3 2013

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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