Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease

Natalia M Lyra E Silva; Rafaella A Gonçalves; Tharick A Pascoal; Ricardo A S Lima-Filho; Elisa de Paula França Resende; Erica L M Vieira; Antonio L Teixeira; Leonardo C de Souza; Julyanna A Peny; Juliana T S Fortuna; Isadora C Furigo; Debora Hashiguchi; Vivian S Miya-Coreixas; Julia R Clarke; Jose F Abisambra; Beatriz M Longo; Jose Donato; Paul E Fraser; Pedro Rosa-Neto; Paulo Caramelli; Sergio T Ferreira; Fernanda G De Felice

doi:10.1038/s41398-021-01349-z

Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease

Natalia M Lyra E Silva, Rafaella A Gonçalves, Tharick A Pascoal, Ricardo A S Lima-Filho, Elisa de Paula França Resende, Erica L M Vieira, Antonio L Teixeira, Leonardo C de Souza, Julyanna A Peny, Juliana T S Fortuna, Isadora C Furigo, Debora Hashiguchi, Vivian S Miya-Coreixas, Julia R Clarke, Jose F Abisambra, Beatriz M Longo, Jose Donato, Paul E Fraser, Pedro Rosa-Neto, Paulo CaramelliSergio T Ferreira, Fernanda G De Felice

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Abstract

Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

Original language	English
Article number	251
Number of pages	15
Journal	Translational Psychiatry
Volume	11
DOIs	https://doi.org/10.1038/s41398-021-01349-z
Publication status	Published - 28 Apr 2021
Externally published	Yes

Bibliographical note

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Funder

This work was supported by grants from National Institute for Translational Neuroscience (INNT/Brazil) (to S.T.F. and F.G.F.), Canadian Institutes of Health Research (to P.F.), National Institute of Health (NIH) (to J.F.A. and University of Kentucky ADC), Department of Defense (to J.F.A.), the Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (to S.T.F., F.G.F., P.C., L.C.S., A.L.T.), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (to S.T.F. and F.G.F.). N.M.L.S., R.A.G., R.A.S.L.F., J.A.P., J.T.S.F., V.S.M.C. received fellowships from Brazilian agencies FAPERJ, CAPES or CNPq.

Keywords

Alzheimer Disease
Amyloid beta-Peptides/metabolism
Animals
Cognitive Dysfunction
Hippocampus/diagnostic imaging
Humans
Interleukin-6
Mice
Plaque, Amyloid

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Lyra E Silva, N. M., Gonçalves, R. A., Pascoal, T. A., Lima-Filho, R. A. S., Resende, E. D. P. F., Vieira, E. L. M., Teixeira, A. L., de Souza, L. C., Peny, J. A., Fortuna, J. T. S., Furigo, I. C., Hashiguchi, D., Miya-Coreixas, V. S., Clarke, J. R., Abisambra, J. F., Longo, B. M., Donato, J., Fraser, P. E., Rosa-Neto, P., ... De Felice, F. G. (2021). Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease. Translational Psychiatry, 11, Article 251. https://doi.org/10.1038/s41398-021-01349-z

Lyra E Silva, NM, Gonçalves, RA, Pascoal, TA, Lima-Filho, RAS, Resende, EDPF, Vieira, ELM, Teixeira, AL, de Souza, LC, Peny, JA, Fortuna, JTS, Furigo, IC, Hashiguchi, D, Miya-Coreixas, VS, Clarke, JR, Abisambra, JF, Longo, BM, Donato, J, Fraser, PE, Rosa-Neto, P, Caramelli, P, Ferreira, ST & De Felice, FG 2021, 'Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease', Translational Psychiatry, vol. 11, 251. https://doi.org/10.1038/s41398-021-01349-z

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abstract = "Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.",

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AU - Pascoal, Tharick A

AU - Lima-Filho, Ricardo A S

AU - Resende, Elisa de Paula França

AU - Vieira, Erica L M

AU - Teixeira, Antonio L

AU - de Souza, Leonardo C

AU - Peny, Julyanna A

AU - Fortuna, Juliana T S

AU - Furigo, Isadora C

AU - Hashiguchi, Debora

AU - Miya-Coreixas, Vivian S

AU - Clarke, Julia R

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AU - Caramelli, Paulo

AU - Ferreira, Sergio T

AU - De Felice, Fernanda G

N1 - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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N2 - Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

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Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease

Abstract

Bibliographical note

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Keywords

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