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

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.

The Multifaceted Neurotoxicity of Astrocytes in Ageing and Age-Related Neurodegenerative Diseases: A Translational Perspective

“…Subpial and RGN astrocytes expressed Nos2, Nos3, and nitrotyrosine in AD hippocampus, frontal, temporal, and entorhinal cortices ( Heneka et al, 2001 ; Lüth et al, 2002 ). IL-6-positive astrocytes were detected in the lateral hypothalamus, cingulate cortex ( Lyra e Silva et al, 2021 ), and prefrontal and temporal cortices ( Bouvier et al, 2016 ). Recent snRNAseq data also gave new insights on astrocyte molecular status in AD.…”

Alterations in Immune-Related Defensin Alpha 4 (DEFA4) Gene Expression in Health and Disease

“…Although the blood state does not necessarily reflect the brain state, IL-6 can cross the blood-brain barrier (BBB) [ 88 ]. The presence of IL-6 at excessive levels in the central nervous system (CNS) may contribute to the neuroinflammation that ultimately leads to brain-related disorders [ 86 ]. On other hand, hypercortisolism was reported to be associated with changes in structure and function of the brain leading to impaired brain ability [ 89 ].…”

Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks

“…Another group of genes (MAP2, METAP2, NFE2L2, SELP, SST, and VEGFA) was down-regulated by hypoglycemia and also downregulated in AD. A number of analyzed genes were suggested as potential targets for AD treatment, including ADIPOQ [83], AQP4 [84], CCL2 [85], CRP [86], EIF2AK3 [87], EPO [88], IGF1 [89], IGF1R [90,91], IGF2 [92,93], IGFBP2 [94], IL6 [95], NFE2L2 [96,97], NOS1 [98], NPY [99,100], PARK7 [101], SERPINE1 [102], SIRT1 [103], SIRT6 [81,104], SLC2A1 [105,106], TNF [107,108], VEGF and VEGFR [109]. The role of these molecules in hypoglycemia-induced brain dysfunction needs further research.…”