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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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1 Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X); Queen’s University, Centre for Neuroscience Studies, Kingston, Canada (GRID:grid.410356.5) (ISNI:0000 0004 1936 8331)
2 Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X); Queen’s University, Centre for Neuroscience Studies, Kingston, Canada (GRID:grid.410356.5) (ISNI:0000 0004 1936 8331); University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938)
3 Douglas Mental Health University Institute, Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Montreal, Canada (GRID:grid.412078.8) (ISNI:0000 0001 2353 5268)
4 Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)
5 Universidade Federal de Minas Gerais, Behavioral and Cognitive Neurology Research Group, Faculdade de Medicina, Belo Horizonte, Brazil (GRID:grid.8430.f) (ISNI:0000 0001 2181 4888); Universidade Federal de Minas Gerais, Hospital das Clínicas, Belo Horizonte, Brazil (GRID:grid.8430.f) (ISNI:0000 0001 2181 4888)
6 Centre of Addiction and Mental Health (CAMH), Toronto, Canada (GRID:grid.155956.b) (ISNI:0000 0000 8793 5925)
7 The University of Texas Health Science Center at Houston, Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401); Santa Casa BH Ensino e Pesquisa, Belo Horizonte, Brazil (GRID:grid.267308.8)
8 Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)
9 Institute of Biomedical Sciences, University of São Paulo, Department of Physiology and Biophysics, São Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)
10 Federal University of São Paulo, Department of Physiology, São Paulo, Brazil (GRID:grid.411249.b) (ISNI:0000 0001 0514 7202)
11 Federal University of Rio de Janeiro, School of Pharmacy, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)
12 Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease University of Florida, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091)
13 University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Department of Medical Biophysics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938)
14 Universidade Federal de Minas Gerais, Behavioral and Cognitive Neurology Research Group, Faculdade de Medicina, Belo Horizonte, Brazil (GRID:grid.8430.f) (ISNI:0000 0001 2181 4888)
15 Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X); Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)
16 Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X); Queen’s University, Centre for Neuroscience Studies, Kingston, Canada (GRID:grid.410356.5) (ISNI:0000 0004 1936 8331); Queen’s University, Department of Psychiatry, Kingston, Canada (GRID:grid.410356.5) (ISNI:0000 0004 1936 8331); Queen’s University, Department of Biomedical and Molecuar Sciences, Kingston, Canada (GRID:grid.410356.5) (ISNI:0000 0004 1936 8331)