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

TitlePro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsSilva NMLyra E, Gonçalves RA, Pascoal TA, Lima-Filho RAS, Resende Ede Paula F, 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
JournalTransl Psychiatry
Volume11
Issue1
Pagination251
Date Published2021 04 28
ISSN2158-3188
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Cognitive Dysfunction, Hippocampus, Humans, Interleukin-6, Mice, Plaque, Amyloid
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.

DOI10.1038/s41398-021-01349-z
Alternate JournalTransl Psychiatry
PubMed ID33911072
PubMed Central IDPMC8080782
Grant List214915 / / Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (Carlos Chagas Filho Foundation for Research Support in the State of Rio de Janeiro) /
218053 / / Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (Carlos Chagas Filho Foundation for Research Support in the State of Rio de Janeiro) /
302686/2014-2 / / Ministry of Science, Technology and Innovation | Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development) /
AZ140097 / / U.S. Department of Defense (United States Department of Defense) /
NIH/NIMHD L32 MD009205-01 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
NIH/NINDS 1R01 NS091329-01 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /