title: TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys.
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.
authors: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
authors: Mychael V
authors: MV
authors: Lourenco
authors: Julia R
authors: JR
authors: Clarke
authors: Rudimar L
authors: RL
authors: Frozza
authors: Theresa R
authors: TR
authors: Bomfim
authors: Letícia
authors: L
authors: Forny-Germano
authors: André F
authors: AF
authors: Batista
authors: Luciana B
authors: LB
authors: Sathler
authors: Jordano
authors: J
authors: Brito-Moreira
authors: Olavo B
authors: OB
authors: Amaral
authors: Cesar A
authors: CA
authors: Silva
authors: Léo
authors: L
authors: Freitas-Correa
authors: Sheila
authors: S
authors: Espírito-Santo
authors: Paula
authors: P
authors: Campello-Costa
authors: Jean-Christophe
authors: JC
authors: Houzel
authors: William L
authors: WL
authors: Klein
authors: Christian
authors: C
authors: Holscher
authors: José B
authors: JB
authors: Carvalheira
authors: Aristobolo M
authors: AM
authors: Silva
authors: Lício A
authors: LA
authors: Velloso
authors: Douglas P
authors: DP
authors: Munoz
authors: Sergio T
authors: ST
authors: Ferreira
authors: Fernanda G
authors: FG
authors: De Felice
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D000882:Haplorhini / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011108:Polymers / Q000737:chemistry / Q000633:toxicity*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; D011108:Polymers; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019892:eIF-2 Kinase