16S sequencing from mouse stool by 5xFAD genotype, high fat high sugar diet, and XPro1595
Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease, are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system, at the blood-brain barrier, and in the gut likely plays an important role in Alzheimer's disease. The cytokine tumor necrosis factor is elevated in AD patients, regulates brain and gut barrier permeability, and is produced in central and peripheral immune cells. Our group previously reported that soluble tumor necrosis factor modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar dysregulates signaling pathways that trigger soluble tumor necrosis factor-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for Alzheimer's disease. We hypothesize that soluble tumor necrosis factor is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis.