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

Lourenco, Mychael V. and Clarke, Julia R. and Frozza, Rudimar L. and Bomfim, Theresa R. and Forny-Germano, Letícia and Batista, André F. and Sathler, Luciana B. and Brito-Moreira, Jordano and Amaral, Olavo B. and Silva, Cesar A. and Freitas-Correa, Léo and Espírito-Santo, Sheila and Campello-Costa, Paula and Houzel, Jean-Christophe and Klein, William L. and Holscher, Christian and Carvalheira, José B. and Silva, Aristobolo M. and Velloso, Lício A. and Munoz, Douglas P. and Ferreira, Sergio T. and De Felice, Fernanda G. (2013) TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-Amyloid oligomers in mice and monkeys. Cell Metabolism, 18 (6). pp. 831-843. ISSN 1932-7420

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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.

Item Type:
Journal Article
Journal or Publication Title:
Cell Metabolism
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1314
Subjects:
ID Code:
68123
Deposited By:
Deposited On:
18 Dec 2013 16:16
Refereed?:
Yes
Published?:
Published
Last Modified:
20 Oct 2020 02:47