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Type: Artigo de periódico
Title: TNF-alpha Mediates PKR-Dependent Memory Impairment and Brain IRS-1 Inhibition Induced by Alzheimer's beta-Amyloid Oligomers in Mice and Monkeys
Author: Lourenco, MV
Clarke, JR
Frozza, RL
Bomfim, TR
Forny-Germano, L
Batista, AF
Sathler, LB
Brito-Moreira, J
Amaral, OB
Silva, CA
Freitas-Correa, L
Espirito-Santo, S
Campello-Costa, P
Houzel, JC
Klein, WL
Holscher, C
Carvalheira, JB
Silva, AM
Velloso, LA
Munoz, DP
Ferreira, ST
De Felice, FG
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 2 alpha (eIF2 alpha-P), and AD brains exhibit elevated phospho-PKR and eIF2 alpha-P levels. Whether and how PKR and eIF2 alpha-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that beta-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor alpha (TNF-alpha)dependent manner, resulting in eIF2 alpha-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2 alpha-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2 alpha-P and cognitive impairment in PKR-/- and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2 alpha-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.
Country: EUA
Editor: Cell Press
Citation: Cell Metabolism. Cell Press, v. 18, n. 6, n. 831, n. 843, 2013.
Rights: fechado
Identifier DOI: 10.1016/j.cmet.2013.11.002
Date Issue: 2013
Appears in Collections:Unicamp - Artigos e Outros Documentos

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