Alzheimers Dement. 2021 Dec;17 Suppl 3 e055753
BACKGROUND: Insulin resistance (IR) and systemic inflammation are risk factors for Alzheimer's disease (AD); however, the molecular and signaling mechanisms underlying this relationship are not well understood. Elevated plasma cytokine levels are associated with increased risk for both AD and IR. The cytokine tumor necrosis factor (TNF) is a major driver of inflammation and is implicated in IR and neurodegeneration. Here, we hypothesize that soluble TNF (solTNF) drives metabolic and immune alterations in the CNS and periphery that promote IR, thereby increasing the risk for AD pathologies.
METHOD: To investigate this hypothesis, 2-month old female 5xFAD mice were fed a high-fat high-carbohydrate diet (HFHC) or a control diet (CD) for 8 weeks. After 1 month, the brain-permeant solTNF inhibitor XPro1595 or a brain-impermeant pan (sol and membrane-bound) TNF inhibitor Etanercept or saline were dosed twice weekly for 4 weeks. Plasma, adipose tissue, and gut were collected for evaluation of IR, metabolic and immune parameters. Molecular markers of insulin signaling, oxidative stress, mitochondrial impairment and inflammation were assessed in relevant brain regions (hippocampus, hypothalamus and cortex).
RESULT: Our preliminary data demonstrate that HFHC-fed 5XFAD mice exhibit increased body weight gain compared to CD groups. Ectopic lipid deposition, as measured by gonadal fat pad and liver volumes, was significantly increased, concurrent to anatomical indicators of intestinal inflammation, including shortened small intestine and colon. HFHC diet promoted systemic inflammation, as measured by increases in the classical pro-inflammatory cytokines IL-6 and TNF. Further, plasma LCN2, a downstream TNF inflammatory molecule associated with insulin insensitivity, hippocampal alterations, and previously observed to be increased in AD patients, was also significantly increased. Ongoing assessments of mRNA and protein expression of insulin signaling and inflammation in the hippocampus and cortex will determine additional effects of TNF in central insulin impairment and AD pathogenesis and will be presented and integrated into the overall findings.
CONCLUSION: Together, these data suggest HFHC diet disrupts peripheral immune and metabolic parameters in the 5XFAD animal model of AD-like pathology, thereby triggering neuroinflammation and insulin insensitivity, conditions which have been implicated in significantly increasing the risk for development of AD in humans.