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

Autor: Lyra E Silva NM; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada., Gonçalves RA; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada., Pascoal TA; Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Douglas Mental Health University Institute, Montreal, Quebec, Canada., Lima-Filho RAS; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Resende EPF; Behavioral and Cognitive Neurology Research Group, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.; Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil., Vieira ELM; Centre of Addiction and Mental Health (CAMH), Toronto, ON, Canada., Teixeira AL; Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.; Santa Casa BH Ensino e Pesquisa, Belo Horizonte, MG, Brazil., de Souza LC; Behavioral and Cognitive Neurology Research Group, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.; Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil., Peny JA; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Fortuna JTS; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Furigo IC; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil., Hashiguchi D; Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil., Miya-Coreixas VS; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Clarke JR; School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Abisambra JF; Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease University of Florida, Gainesville, FL, USA., Longo BM; Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil., Donato J Jr; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil., Fraser PE; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Rosa-Neto P; Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Douglas Mental Health University Institute, Montreal, Quebec, Canada., Caramelli P; Behavioral and Cognitive Neurology Research Group, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil., Ferreira ST; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. ferreira@bioqmed.ufrj.br.; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. ferreira@bioqmed.ufrj.br., De Felice FG; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. felice@bioqmed.ufrj.br.; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada. felice@bioqmed.ufrj.br.; Department of Psychiatry, Queen's University, Kingston, ON, Canada. felice@bioqmed.ufrj.br.; Department of Biomedical and Molecuar Sciences, Queen's University, Kingston, ON, Canada. felice@bioqmed.ufrj.br.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2021 Apr 28; Vol. 11 (1), pp. 251. Date of Electronic Publication: 2021 Apr 28.
DOI: 10.1038/s41398-021-01349-z
Abstrakt: 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.
Databáze: MEDLINE