TNF-α Mediates PKR-Dependent Memory Impairment and Brain IRS-1 Inhibition Induced by Alzheimer's β-Amyloid Oligomers in Mice and Monkeys

被引：362

作者：

Lourenco, Mychael V. ^{[1
]}

Clarke, Julia R. ^{[1
]}

Frozza, Rudimar L. ^{[1
]}

Bomfim, Theresa R. ^{[1
]}

Forny-Germano, Leticia ^{[1
]}

Batista, Andre F. ^{[1
]}

Sathler, Luciana B. ^{[1
]}

Brito-Moreira, Jordano ^{[1
]}

Amaral, Olavo B. ^{[1
]}

Silva, Cesar A. ^{[1
]}

Freitas-Correa, Leo ^{[1
]}

Espirito-Santo, Sheila ^{[3
]}

Campello-Costa, Paula ^{[3
]}

Houzel, Jean-Christophe ^{[2
]}

Klein, William L. ^{[4
]}

Holscher, Christian ^{[5
]}

Carvalheira, Jose B. ^{[6
]}

Silva, Aristobolo M. ^{[7
,8
]}

Velloso, Licio A. ^{[9
]}

Munoz, Douglas P. ^{[10
]}

Ferreira, Sergio T. ^{[1
]}

De Felice, Fernanda G. ^{[1
]}

机构：

[1] Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil

[2] Univ Fed Rio de Janeiro, Inst Biomed Sci, BR-21941902 Rio De Janeiro, RJ, Brazil

[3] Univ Fed Fluminense, Inst Biol, BR-24001970 Niteroi, RJ, Brazil

[4] Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA

[5] Univ Lancaster, Fac Hlth & Med, Lancaster LA1 4YQ, England

[6] Univ Estadual Campinas, Fac Med Sci, Dept Internal Med, BR-13084761 Campinas, SP, Brazil

[7] Univ Fed Minas Gerais, Inst Biol Sci, BR-31270901 Belo Horizonte, MG, Brazil

[8] Fiocruz MS, Rene Rachou Res Ctr, BR-30190002 Belo Horizonte, MG, Brazil

[9] Univ Estadual Campinas, DCM FCM UNICAMP, Obes & Comorbid Res Ctr, Lab Cell Signalling, BR-13084761 Campinas, SP, Brazil

[10] Queens Univ, Ctr Neurosci Studies, Kingston, ON K7L 3N6, Canada

来源：

CELL METABOLISM | 2013年 / 18卷 / 06期

关键词：

ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; TYROSINE KINASE-ACTIVITY; D-ASPARTATE RECEPTOR; INSULIN-RESISTANCE; COGNITIVE IMPAIRMENT; SYNAPTIC PLASTICITY; INTRANASAL INSULIN; MOUSE MODEL; MOLECULAR-BASIS;

D O I：

10.1016/j.cmet.2013.11.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 2 alpha (eIF2 alpha-P), and AD brains exhibit elevated phospho-PKR and eIF2 alpha-P levels. Whether and how PKR and eIF2 alpha-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that beta-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor alpha (TNF-alpha)dependent manner, resulting in eIF2 alpha-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2 alpha-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2 alpha-P and cognitive impairment in PKR-/- and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2 alpha-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.

引用

页码：831 / 843

页数：13

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