P025 - TNF AS A MEDIATOR OF IMMUNE AND METABOLIC ALTERATIONS IN THE 5XFAD MOUSE MODEL OF ALZHEIMER’S DISEASE (ID 1228)
Abstract
Aims
Objectives: Elevated circulating cytokines are associated with increased risk for cognitive and metabolic impairment. Tumor necrosis factor (TNF) is a driver of immune responses in the periphery and brain, and is implicated in neurodegeneration. We aim to evaluate the role of TNF signaling on the metabolic and immunologic alterations in the brain and periphery that increases the risk for AD.
Methods
Methods: Two-month old female 5xFAD mice were fed a high-fat, high-carbohydrate diet (HFHC) or a matched control diet (CD) for 8 weeks. After 1 month, the brain-permeant solTNF inhibitor XPro1595 or the brain-impermeant non-selective TNF inhibitor Enbrel were dosed twice weekly for 4 weeks. Plasma, adipose tissue, liver and gut were collected for evaluation of metabolic and immune parameters. Molecular markers of insulin signaling and neuroinflammation were assessed in the hippocampus, hypothalamus and cortex.
Results
Results: HFHC diet increases body weight, gonadal tissue and liver compared to CD groups. HFHC diet promotes a decrease in cecum weight, and small intestine and colon lengths. HFHC elevates circulating insulin, leptin, CCL2 and CXCL2 and decreases plasma IL-2. Enbrel increases liver weight and decreases circulating IL-2 in CD mice. Ongoing behavioral testing and assessments of mRNA and protein expression of insulin signaling and inflammation in the hippocampus, hypothalamus and cortex will determine additional effects of TNF on metabolic and immune impairment in the brain
Conclusions
Conclusion: Together, these data suggest HFHC diet disrupts peripheral immune and metabolic parameters in the 5XFAD animal model of AD, and create conditions implicated in increased risk for AD development.
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