Blocking soluble TNF decreases diet‐induced hyperglycemia and modulates immune alterations in 5xFAD animal model of Alzheimer’s disease

Background Regulatory interactions between the gut and brain are essential for energy homeostasis across systems. Current evidence indicates high-fat, high-carbohydrate diets (HFHC) impact Alzheimer’s disease (AD) pathophysiology, however, mechanisms underlying this association poorly understood. We hypothesize that (1) Tumor Necrosis Factor (TNF) mediates metabolic inflammation in an obesogenic environment with impacts gut-brain axis (2) HFHC interacts AD-relevant genetic background to promote immune dysregulation accelerates pathological behavioral dysfunction animal model of AD. Method To investigate effects chronic systemic on AD-associated pathology, 2-month old female 5xFAD mice were fed or a control (CD) 8 weeks. One month following dietary intervention, brain-permeant soluble TNF inhibitor XPro1595 brain-impermeant pan (sol membrane-bound) Etanercept (Enbrel, Amgen-Wyeth) vehicle (saline) dosed twice weekly 4 Behavioral test performed assess cognitive parameters. Plasma, collected evaluation insulin impairment, Cortical tissues subjected RNAseq analysis determine gene pathways modified by diet, genotype, inhibition. Result promoted syndrome features associated increases adiposity, body weight, plasma glucose, cholesterol, leptin, insulin. inhibition did not rescue diet-induced increases, however XPro specifically reduced while Enbrel increased HOMA-IR HFHC-fed mice. diet circulating IL-6, CXCL1, CXCL2 CCL2 neutralization either drug decreased IL-6 groups. In colon, CCL3 blockade colonic IL-15 Ongoing assessment, cortical transcriptional analysis, hippocampal protein profiles signaling inflammatory markers will additional 5XFAD Conclusion Collectively, these results suggest modulates induced consumption neurodegeneration neuroinflammation. Blocking decreases hyperglycemia triggered during diet-induce obesity. Future studies focusing provide targets new therapeutics against neurological disease.