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

Theresa R Bomfim, Leticia Forny-Germano, Luciana B Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A Silverman, Hala Kazi, Helen M Melo, Paula McClean, Christian Holscher, Steven E Arnold, Konrad Talbot, William L Klein, Douglas P Munoz, Sergio T Ferreira, Fernanda G De Felice

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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.
LanguageEnglish
Pages1339-53
JournalThe Journal of clinical investigation
Volume122
Issue number4
DOIs
Publication statusPublished - 2012

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Amyloid beta-Peptides
Alzheimer Disease
Insulin
Brain
Serine
Phosphorylation
Axonal Transport
Macaca fascicularis
Brain Diseases
Cognition
Insulin Resistance
Hippocampus
Tumor Necrosis Factor-alpha
Pathology
Neurons
Injections

Cite this

Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J-C., Decker, H., ... 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. The Journal of clinical investigation, 122(4), 1339-53. https://doi.org/10.1172/JCI57256
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 ; 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: The Journal of clinical investigation. 2012 ; Vol. 122, No. 4. pp. 1339-53.
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Bomfim, TR, Forny-Germano, L, Sathler, LB, Brito-Moreira, J, Houzel, J-C, Decker, H, Silverman, MA, Kazi, H, Melo, HM, McClean, P, 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.', The Journal of clinical investigation, vol. 122, no. 4, pp. 1339-53. https://doi.org/10.1172/JCI57256

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; Holscher, Christian; Arnold, Steven E; Talbot, Konrad; Klein, William L; Munoz, Douglas P; Ferreira, Sergio T; De Felice, Fernanda G.

In: The Journal of clinical investigation, Vol. 122, No. 4, 2012, p. 1339-53.

Research output: Contribution to journalArticle

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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

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

Y1 - 2012

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.

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M3 - Article

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