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

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

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 languageEnglish (US)
Article number251
JournalTranslational psychiatry
Volume11
Issue number1
DOIs
StatePublished - Jun 2021
Externally publishedYes

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Fingerprint

Dive into the research topics of 'Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer’s disease'. Together they form a unique fingerprint.

Cite this