Artículos de revistas
Tnf-α Mediates Pkr-dependent Memory Impairment And Brain Irs-1 Inhibition Induced By Alzheimer's β-amyloid Oligomers In Mice And Monkeys
Registro en:
Cell Metabolism. , v. 18, n. 6, p. 831 - 843, 2013.
15504131
10.1016/j.cmet.2013.11.002
2-s2.0-84889656503
Autor
Lourenco M.V.
Clarke J.R.
Frozza R.L.
Bomfim T.R.
Forny-Germano L.
Batista A.F.
Sathler L.B.
Brito-Moreira J.
Amaral O.B.
Silva C.A.
Freitas-Correa L.
Espirito-Santo S.
Campello-Costa P.
Houzel J.-C.
Klein W.L.
Holscher C.
Carvalheira J.B.
Silva A.M.
Velloso L.A.
Munoz D.P.
Ferreira S.T.
De Felice F.G.
Institución
Resumen
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. 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