TNF-α Mediates PKR-Dependent Memory Impairment and Brain IRS-1 Inhibition Induced by Alzheimer’s β-Amyloid Oligomers in Mice and Monkeys
| Autor: | Luciana B. Sathler, William L. Klein, Julia R. Clarke, Rudimar Luiz Frozza, Jean-Christophe Houzel, Cesar A. Silva, Aristóbolo M. Silva, Douglas P. Munoz, Andre F. Batista, Léo Freitas-Correa, Fernanda G. De Felice, Leticia Forny-Germano, Sergio T. Ferreira, José B.C. Carvalheira, Mychael V. Lourenco, Jordano Brito-Moreira, Theresa R. Bomfim, Olavo B. Amaral, Paula Campello-Costa, Christian Hölscher, Sheila Espírito-Santo, Licio A. Velloso |
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| Jazyk: | angličtina |
| Předmět: |
medicine.medical_specialty
Polymers Physiology viruses environment and public health Proinflammatory cytokine Synapse Mice eIF-2 Kinase 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Insulin receptor substrate Internal medicine medicine Animals Hypoglycemic Agents Phosphorylation Protein kinase A Receptor Molecular Biology 030304 developmental biology Mice Knockout Neurons Memory Disorders 0303 health sciences Amyloid beta-Peptides biology Tumor Necrosis Factor-alpha Chemistry Brain virus diseases Haplorhini Cell Biology biochemical phenomena metabolism and nutrition Protein kinase R Disease Models Animal Insulin receptor enzymes and coenzymes (carbohydrates) Endocrinology Receptors Tumor Necrosis Factor Type I Synapses Immunology Insulin Receptor Substrate Proteins biology.protein Tumor necrosis factor alpha 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cell Metabolism. (6):831-843 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2013.11.002 |
| Popis: | SummaryAlzheimer’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. |
| Databáze: | OpenAIRE |
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