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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers

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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. / Bomfim, Theresa R.; Forny-Germano, Leticia; Sathler, Luciana B.; Brito-Moreira, Jordano; Houzel, Jean-Christophe; Decker, Helena; Silverman, Michael A.; Kazi, Hala; Melo, Helen M.; McClean, Paula L.; Holscher, Christian; Arnold, Steven E.; Talbot, Konrad; Klein, William L.; Munoz, Douglas P.; Ferreira, Sergio T.; De Felice, Fernanda G.

In: Journal of Clinical Investigation, Vol. 122, No. 4, 02.04.2012, p. 1339-1353.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Bomfim, TR, Forny-Germano, L, Sathler, LB, Brito-Moreira, J, Houzel, J-C, Decker, H, Silverman, MA, Kazi, H, Melo, HM, McClean, PL, Holscher, C, Arnold, SE, Talbot, K, Klein, WL, Munoz, DP, Ferreira, ST & De Felice, FG 2012, 'An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers', Journal of Clinical Investigation, vol. 122, no. 4, pp. 1339-1353. https://doi.org/10.1172/JCI57256

APA

Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J-C., Decker, H., Silverman, M. A., Kazi, H., Melo, H. M., McClean, P. L., Holscher, C., Arnold, S. E., Talbot, K., Klein, W. L., Munoz, D. P., Ferreira, S. T., & De Felice, F. G. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. Journal of Clinical Investigation, 122(4), 1339-1353. https://doi.org/10.1172/JCI57256

Vancouver

Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel J-C, Decker H et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. Journal of Clinical Investigation. 2012 Apr 2;122(4):1339-1353. https://doi.org/10.1172/JCI57256

Author

Bomfim, Theresa R. ; Forny-Germano, Leticia ; Sathler, Luciana B. ; Brito-Moreira, Jordano ; Houzel, Jean-Christophe ; Decker, Helena ; Silverman, Michael A. ; Kazi, Hala ; Melo, Helen M. ; McClean, Paula L. ; Holscher, Christian ; Arnold, Steven E. ; Talbot, Konrad ; Klein, William L. ; Munoz, Douglas P. ; Ferreira, Sergio T. ; De Felice, Fernanda G. / An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 4. pp. 1339-1353.

Bibtex

@article{9ed730a5968f4cfbba89aa0da28efaac,
title = "An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers",
abstract = "Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.",
keywords = "Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Animals, Antibodies, Monoclonal, Cells, Cultured, Female, Hippocampus, Humans, Hypoglycemic Agents, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, MAP Kinase Signaling System, Macaca fascicularis, Male, Maze Learning, Memory Disorders, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Neurons, Peptides, Phosphorylation, Protein Processing, Post-Translational, Rats, Venoms",
author = "Bomfim, {Theresa R.} and Leticia Forny-Germano and Sathler, {Luciana B.} and Jordano Brito-Moreira and Jean-Christophe Houzel and Helena Decker and Silverman, {Michael A.} and Hala Kazi and Melo, {Helen M.} and McClean, {Paula L.} and Christian Holscher and Arnold, {Steven E.} and Konrad Talbot and Klein, {William L.} and Munoz, {Douglas P.} and Ferreira, {Sergio T.} and {De Felice}, {Fernanda G.}",
year = "2012",
month = apr,
day = "2",
doi = "10.1172/JCI57256",
language = "English",
volume = "122",
pages = "1339--1353",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

RIS

TY - JOUR

T1 - An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers

AU - Bomfim, Theresa R.

AU - Forny-Germano, Leticia

AU - Sathler, Luciana B.

AU - Brito-Moreira, Jordano

AU - Houzel, Jean-Christophe

AU - Decker, Helena

AU - Silverman, Michael A.

AU - Kazi, Hala

AU - Melo, Helen M.

AU - McClean, Paula L.

AU - Holscher, Christian

AU - Arnold, Steven E.

AU - Talbot, Konrad

AU - Klein, William L.

AU - Munoz, Douglas P.

AU - Ferreira, Sergio T.

AU - De Felice, Fernanda G.

PY - 2012/4/2

Y1 - 2012/4/2

N2 - Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.

AB - Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.

KW - Aged

KW - Aged, 80 and over

KW - Alzheimer Disease

KW - Amyloid beta-Peptides

KW - Animals

KW - Antibodies, Monoclonal

KW - Cells, Cultured

KW - Female

KW - Hippocampus

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin

KW - Insulin Receptor Substrate Proteins

KW - Insulin Resistance

KW - MAP Kinase Signaling System

KW - Macaca fascicularis

KW - Male

KW - Maze Learning

KW - Memory Disorders

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Middle Aged

KW - Neurons

KW - Peptides

KW - Phosphorylation

KW - Protein Processing, Post-Translational

KW - Rats

KW - Venoms

U2 - 10.1172/JCI57256

DO - 10.1172/JCI57256

M3 - Journal article

C2 - 22476196

VL - 122

SP - 1339

EP - 1353

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -