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

Research output: Contribution to journalJournal article

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  • 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
  • José B. Carvalheira
  • Aristobolo M. Silva
  • Lício A. Velloso
  • Douglas P. Munoz
  • Sergio T. Ferreira
  • Fernanda G. De Felice
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<mark>Journal publication date</mark>3/12/2013
<mark>Journal</mark>Cell Metabolism
Issue number6
Volume18
Number of pages13
Pages (from-to)831-843
Publication statusPublished
Original languageEnglish

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.