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TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys.
Cell Metab 2013; 18(6):831-43CM

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+Show Affiliations

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24315369

Citation

Lourenco, Mychael V., et al. "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, vol. 18, no. 6, 2013, pp. 831-43.
Lourenco MV, Clarke JR, Frozza RL, et al. TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys. Cell Metab. 2013;18(6):831-43.
Lourenco, M. V., Clarke, J. R., Frozza, R. L., Bomfim, T. R., Forny-Germano, L., Batista, A. F., ... De Felice, F. 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. 831-43. doi:10.1016/j.cmet.2013.11.002.
Lourenco MV, et al. TNF-α Mediates PKR-dependent Memory Impairment and Brain IRS-1 Inhibition Induced By Alzheimer's Β-amyloid Oligomers in Mice and Monkeys. Cell Metab. 2013 Dec 3;18(6):831-43. PubMed PMID: 24315369.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys. AU - Lourenco,Mychael V, AU - Clarke,Julia R, AU - Frozza,Rudimar L, AU - Bomfim,Theresa R, AU - Forny-Germano,Letícia, AU - Batista,André F, AU - Sathler,Luciana B, AU - Brito-Moreira,Jordano, AU - Amaral,Olavo B, AU - Silva,Cesar A, AU - Freitas-Correa,Léo, AU - Espírito-Santo,Sheila, AU - Campello-Costa,Paula, AU - Houzel,Jean-Christophe, AU - Klein,William L, AU - Holscher,Christian, AU - Carvalheira,José B, AU - Silva,Aristobolo M, AU - Velloso,Lício A, AU - Munoz,Douglas P, AU - Ferreira,Sergio T, AU - De Felice,Fernanda G, PY - 2012/08/02/received PY - 2013/09/17/revised PY - 2013/10/18/accepted PY - 2013/12/10/entrez PY - 2013/12/10/pubmed PY - 2014/7/16/medline SP - 831 EP - 43 JF - Cell metabolism JO - Cell Metab. VL - 18 IS - 6 N2 - 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. SN - 1932-7420 UR - https://www.unboundmedicine.com/medline/citation/24315369/TNF_α_mediates_PKR_dependent_memory_impairment_and_brain_IRS_1_inhibition_induced_by_Alzheimer's_β_amyloid_oligomers_in_mice_and_monkeys_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1550-4131(13)00450-6 DB - PRIME DP - Unbound Medicine ER -