Soluble TNF in metabolic dysfunction and BBB alterations in a mouse model of Alzheimer's Disease
Lori N Eidson, PhD, Kathryn P. MacPherson, PhD, Mary K Herrick, BS, Maria Elizabeth de Sousa Rodrigues, PhD, Danielle Oliver, BS, Sean D Kelly, BS, Yuan Yang, MD, Jianjun Chang, MS, Lindsey Sniffen and Malu G. Tansey, PhD Emory University School of Medicine, Atlanta, GA, USA
Peripheral immune cell signaling plays an important role in neuroinflammatory diseases, such as Alzheimer's disease (AD) and dysregulation of several signaling pathways in type 2 diabetes and obesity trigger immune and metabolic responses that may worsen energetic metabolism. Cytokine and chemokine mechanisms regulate peripheral immune cell trafficking to inflamed tissues, including the brain. The cytokine, tumor necrosis factor (TNF), is elevated in AD patients, regulates blood-brain barrier permeability, and is produced by central and peripheral immune cells. Further, TNF mediates conditions involved in metabolic syndrome. We hypothesize that soluble TNF (sTNF) is a key mediator of peripheral immune cell contributions to AD-like pathology and metabolic dysfuction. Here we aim to determine the effect of chronic high-fat high-carbohydrate (HFHC) diet-induced peripheral inflammation on neuroinflammation and neuronal health in a model of AD. 5xFAD female mice were fed a high-fat high-carbohydrate (HFHC) or a control diet (CD) for 8 weeks. After 4 weeks of diet, XPro®1595, a BBB-permeant peptide, was used to inhibit soluble TNF signaling. Tight junction proteins and central inflammatory gene expression were evaluated by qPCR. Immune cell populations were assessed using flow cytometry. 5xFAD mice fed a HFHC diet had increased hippocampal TNF mRNA expression and XPro eliminated this effect. Mice given HFHC diet had increased hippocampal ZO-1 mRNA expression compared to CD-fed mice given saline and XPro reversed this effect. 5xFAD mice had increased T cell populations in the brain when fed HFHC, and in HFHC diet-fed Tg mice as compared with HFHC nonTg mice. An increase in Ly6C+ T cells was observed in HFHC diet-fed Tg mice versus CD fed mice, suggesting an increased migration of T cell populations into the brain. Experiments are ongoing to assess additional effects of TNF in AD pathogenesis. Diet induced obesity alters immune cell populations in 5xFAD mice and promotes BBB associated alterations that may impact neuroinflammation and increase the risks for AD pathology.
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