Targeting soluble tumor necrosis factor as a potential intervention to lower risk for late-onset Alzheimer's disease associated with obesity, metabolic syndrome, and type 2 diabetes

• Type of Material: Article
• Authors: Maria Elizabeth Rodrigues, Emory University; Madelyn C. Houser, Emory University; Douglas Walker, Emory University; Dean Jones, Emory University; Jianjun Chang, Emory University; Christopher J. Barnum, Emory University; Malu Tansey, Emory University
• Language: English
• Date: 2019-12-31
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13195-019-0546-4
• Title of Journal or Parent Work: ALZHEIMERS RESEARCH & THERAPY
• Volume: 12
• Issue: 1
• Start Page: 1
• End Page: 1
• Grant/Funding Information: Partial funding for this work was provided by a grant from the National Institute of Aging (NIA) at the National Institutes of Health (1RF1AG051514 and 1RF1AG057247, MGT). The Emory Multiplexed Immunoassay Core (EMIC) is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the National Center for Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.
• Keywords: Neurosciences; BRAIN; INDUCED INSULIN-RESISTANCE; Lipocalin-2; Insulin; FACTOR-ALPHA; Soluble tumor necrosis factor; LIPOCALIN 2; ARTHRITIS; Proteoglycans; Gut; TNF-ALPHA; LIVER; Neuroactive metabolites; Clinical Neurology; Purines; Metabolic inflammation; Neurosciences & Neurology; RECEPTOR; INACTIVATION; Life Sciences & Biomedicine; INFLAMMATION; Liver; Science & Technology; Metabolomics
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Neuroscience; Psychology, Cognitive; Health Sciences, Public Health

Abstract

Background: Insulin impairment and inflammation are two features common to type 2 diabetes and Alzheimer's disease; however, the molecular and signaling interactions underlying this relationship are not well understood. Mounting evidence point to the associations between the disruption of metabolite processing in insulin impairment and neurodegenerative conditions such as Alzheimer's. Although the brain depends partially on metabolites processed in the periphery, to date, little is known about how soluble tumor necrosis factor signaling (solTNF) impacts integrated peripheral immune and metabolic feedback signals in states of energy overload and insulin insensitivity. Methods: C57Bl/6J mice were fed a high-fat high-carbohydrate diet (HFHC) for 14 weeks. The brain-permeant biologic XPro1595® was used to block solTNF-dependent pathways. Metabolic and immune alterations were evaluated in the gut, liver, and brain. Behavioral tests were performed. Untargeted metabolomics was carried out in the plasma and liver. Results: HFHC diet promotes central insulin impairment and dysregulation of immune-modulatory gene expressed in the brain. Alteration of metabolites associated with type 2 diabetes and Alzheimer's such as butanoate, glutamate, biopterin, branched-chain amino acids, purines, and proteoglycan metabolism was observed in HFHC-fed mice. solTNF inhibition ameliorates hepatic metabolic disturbances and hepatic and intestinal lipocalin-2 levels, and decreases insulin impairment in the brain and behavioral deficits associated with HFHC diet. Conclusions: Our novel findings suggest that HFHC diet impacts central insulin signaling and immune-metabolic interactions in a solTNF-dependent manner to increase the risk for neurodegenerative conditions. Our novel findings indicate that selective solTNF neutralization can ameliorate peripheral and central diet-induced insulin impairment and identify lipocalin-2 as a potential target for therapeutic intervention to target inflammation and insulin disturbances in obesogenic environments. Collectively, our findings identify solTNF as a potential target for therapeutic intervention in inflammatory states and insulin disturbances in obesogenic environments to lower risk for AD.