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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / toxicity*
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Animals
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Brain / drug effects*
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Brain / metabolism
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Disease Models, Animal
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Haplorhini / metabolism
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Hypoglycemic Agents / pharmacology
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Insulin Receptor Substrate Proteins / antagonists & inhibitors
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Insulin Receptor Substrate Proteins / metabolism*
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Memory Disorders / metabolism
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Memory Disorders / pathology
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Mice
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Mice, Knockout
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Neurons / drug effects
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Neurons / metabolism
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Phosphorylation / drug effects
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Polymers / chemistry
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Polymers / toxicity*
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Receptors, Tumor Necrosis Factor, Type I / deficiency
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Signal Transduction / drug effects
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Synapses / drug effects
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Synapses / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism*
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eIF-2 Kinase / deficiency
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism*
Substances
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Amyloid beta-Peptides
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Hypoglycemic Agents
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Insulin Receptor Substrate Proteins
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Polymers
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Receptors, Tumor Necrosis Factor, Type I
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Tnfrsf1a protein, mouse
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Tumor Necrosis Factor-alpha
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eIF-2 Kinase