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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

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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. / Lourenco, Mychael V.; Clarke, Julia R.; Frozza, Rudimar L. et al.
In: Cell Metabolism, Vol. 18, No. 6, 03.12.2013, p. 831-843.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Lourenco, MV, Clarke, JR, Frozza, RL, Bomfim, TR, Forny-Germano, L, Batista, AF, Sathler, LB, Brito-Moreira, J, Amaral, OB, Silva, CA, Freitas-Correa, L, Espírito-Santo, S, Campello-Costa, P, Houzel, J-C, Klein, WL, Holscher, C, Carvalheira, JB, Silva, AM, Velloso, LA, Munoz, DP, Ferreira, ST & De Felice, FG 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, vol. 18, no. 6, pp. 831-843. https://doi.org/10.1016/j.cmet.2013.11.002

APA

Lourenco, M. V., Clarke, J. R., Frozza, R. L., Bomfim, T. R., Forny-Germano, L., Batista, A. F., Sathler, L. B., Brito-Moreira, J., Amaral, O. B., Silva, C. A., Freitas-Correa, L., Espírito-Santo, S., Campello-Costa, P., Houzel, J-C., Klein, W. L., Holscher, C., Carvalheira, J. B., Silva, A. M., Velloso, L. A., ... 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), 831-843. https://doi.org/10.1016/j.cmet.2013.11.002

Vancouver

Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF 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. 2013 Dec 3;18(6):831-843. doi: 10.1016/j.cmet.2013.11.002

Author

Lourenco, Mychael V. ; Clarke, Julia R. ; Frozza, Rudimar L. 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. In: Cell Metabolism. 2013 ; Vol. 18, No. 6. pp. 831-843.

Bibtex

@article{aae594fb14d646488c794539937b3a16,
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.",
author = "Lourenco, {Mychael V.} and Clarke, {Julia R.} and Frozza, {Rudimar L.} and Bomfim, {Theresa R.} and Let{\'i}cia Forny-Germano and Batista, {Andr{\'e} F.} and Sathler, {Luciana B.} and Jordano Brito-Moreira and Amaral, {Olavo B.} and Silva, {Cesar A.} and L{\'e}o Freitas-Correa and Sheila Esp{\'i}rito-Santo and Paula Campello-Costa and Jean-Christophe Houzel and Klein, {William L.} and Christian Holscher and Carvalheira, {Jos{\'e} B.} and Silva, {Aristobolo M.} and Velloso, {L{\'i}cio A.} and Munoz, {Douglas P.} and Ferreira, {Sergio T.} and {De Felice}, {Fernanda G.}",
year = "2013",
month = dec,
day = "3",
doi = "10.1016/j.cmet.2013.11.002",
language = "English",
volume = "18",
pages = "831--843",
journal = "Cell Metabolism",
issn = "1932-7420",
publisher = "Cell Press",
number = "6",

}

RIS

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 - 2013/12/3

Y1 - 2013/12/3

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.

AB - 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.

U2 - 10.1016/j.cmet.2013.11.002

DO - 10.1016/j.cmet.2013.11.002

M3 - Journal article

C2 - 24315369

VL - 18

SP - 831

EP - 843

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1932-7420

IS - 6

ER -