Translational potential of JAX humanized APOE mice: Peripheral interferon gamma induces systemic immuno-metabolic dysfunction

Background: Inflammation is a well-documented feature of Alzheimer’s disease (AD) in human brain. Previous findings from our group demonstrated upregulated immune transcripts in the AD brain as well as sex differences in immune transcript levels during pre-clinical midlife aging. Using our humanized APOE mouse model, we identified elevated immune transcripts in the female brain including interferon signaling genes, CD3, CD4, and MHCII. We hypothesized that activation via increased interferon gamma (IFN-γ) during endocrine aging may disrupt the immune-metabolic balance in the brain and therefore advance changes in grey and white matter. With this study, we test the hypothesis that increased levels of peripheral IFN-γ induces genotype dependent immuno-metabolic changes in the JAX humanized APOE (hAPOE) mouse model. Method: To determine the role of IFN-γ in female midlife aging and AD risk, pre-menopausal and peri-menopausal hAPOE mice were intraperitoneally treated with recombinant IFN-γ for 9 days. Immunophenotyping using multi-color flow cytometry was conducted microglial reactivity, phagocytosis, neutral lipid content, oxidative stress, and the presence of lymphocytes were determined. Structural and diffusion weighted analysis using MRI was conducted to evaluate grey and white matter structural integrity in the brain. ELISA assays were conducted to assess the presence of beta amyloid 40 and 42 and levels of pro-inflammatory cytokines. Result: IFN-γ treated animals exhibited upregulation of markers that perpetuate neuroinflammation and white matter catabolism including MHCII, CD8, pHrodo, and BODIPY. Peripheral immune effects were genotype dependent while immune signaling in brain largely exhibited treatment-dependent effects. Fasting blood glucose levels were significantly increased by IFN-γ consistent with an accelerated aging profile. Diffusion metrics including mean and radial kurtosis in addition to mean, axial, and radial diffusivity were greater in IFN-treated animals. Conclusion: Peripheral increase of interferon gamma signaling during female endocrine aging in hAPOE mice induced 1) dysfunction of metabolic systems and neuroinflammatory response and 2) decreases in white and grey matter microstructural integrity throughout the brain. These outcomes support the investigation of therapeutic strategies targeting interferon signaling pathways at the earliest stages of midlife aging to reduce risk of AD or delay AD onset.